Among those contributing to the issue was Composer and musicologist Nicolas Slonimsky, who conducted premiere performances of works of Ives and Varèse in the 1930s. He became friends with Zappa in the 1980s, and said, "I admire everything Frank does, because he practically created the new musical millennium. He does beautiful, beautiful work ... It has been my luck to have lived to see the emergence of this totally new type of music."

Frank, the eldest of four children, was raised in an Italian-American household where Italian was often spoken by his grandparents. The family moved often because his father, a Chemist and Mathematician, worked in the defense industry. After a time in Florida in the 1940s, the family returned to Maryland, where Zappa's father worked at the Edgewood Arsenal chemical warfare facility of the Aberdeen Proving Ground. Due to their home's proximity to the arsenal, which stored mustard gas, gas masks were kept in the home in case of an accident. This had a profound effect on Zappa, and references to germs, germ warfare and the defense industry occur throughout his work.

Zappa grew up influenced by avant-garde composers such as Edgard Varèse, Igor Stravinsky, and Anton Webern; 1950s blues artists Clarence "Gatemouth" Brown, Guitar Slim, Johnny Guitar Watson, and B.B. King; R&B and doo-wop groups (particularly local pachuco groups); and modern jazz. His own heterogeneous ethnic background, and the diverse social and cultural mix in and around greater Los Angeles, were crucial in the formation of Zappa as a practitioner of underground music and of his later distrustful and openly critical attitude towards "mainstream" social, political and musical movements. He frequently lampooned musical fads like psychedelia, rock opera and disco. Television also exerted a strong influence, as demonstrated by quotations from show themes and advertising jingles found in his later works.

Nasal imagery and references appear in his music and lyrics, as well as in the collage album covers created by his long-time collaborator Cal Schenkel. Zappa believed his childhood diseases might have been due to exposure to mustard gas, released by the nearby chemical warfare facility. His health worsened when he lived in Baltimore. In 1952, his family relocated for reasons of health. They next moved to Monterey, California, where his father taught metallurgy at the Naval Postgraduate School. They soon moved to Claremont, California, then to El Cajon, before finally settling in San Diego.

By 1956, the Zappa family had moved to Lancaster, a small aerospace and farming town in the Antelope Valley of the Mojave Desert close to Edwards Air Force Base; he would later refer to Lancaster in the 1973 track "Village of the Sun". Zappa's mother encouraged him in his musical interests. Although she disliked Varèse's music, she was indulgent enough to give her son a long distance call to the Composer as a 15th birthday present. Unfortunately, Varèse was in Europe at the time, so Zappa spoke to the composer's wife and she suggested he call back later. In a letter Varèse thanked him for his interest, and told him about a composition he was working on called "Déserts". Living in the desert town of Lancaster, Zappa found this very exciting. Varèse invited him to visit if he ever came to New York. The meeting never took place (Varèse died in 1965), but Zappa framed the letter and kept it on display for the rest of his life.

At Antelope Valley High School, Zappa met Don Glen Vliet (who later changed his name to Don Van Vliet and adopted the stage name Captain Beefheart). Zappa and Vliet became close friends, sharing an interest in R&B records and influencing each other musically throughout their careers. Around the same time, Zappa started playing drums in a local band, the Blackouts. The band was racially diverse and included Euclid James "Motorhead" Sherwood who later became a member of the Mothers of Invention. Zappa's interest in the guitar grew, and in 1957 he was given his first instrument. Among his early influences were Johnny "Guitar" Watson, Howlin' Wolf and Clarence "Gatemouth" Brown. (In the 1970s/80s, he invited Watson to perform on several albums.) Zappa considered soloing as the equivalent of forming "air sculptures", and developed an eclectic, innovative and highly personal style.

Zappa's interest in composing and arranging flourished in his last high-school years. By his final year, he was writing, arranging and conducting avant-garde performance pieces for the school orchestra. He graduated from Antelope Valley High School in 1958, and later acknowledged two of his music teachers on the sleeve of the 1966 album Freak Out! Due to his family's frequent moves, Zappa attended at least six different high schools, and as a student he was often bored and given to distracting the rest of the class with Juvenile antics. In 1959, he attended Chaffey College but left after one semester, and maintained thereafter a disdain for formal education, taking his children out of school at age 15 and refusing to pay for their college.

Zappa was married to Kathryn J. "Kay" Sherman from 1960 to 1963. In 1967, he married Adelaide Gail Sloatman. He and his second wife had four children: Moon, Dweezil, Ahmet and Diva.

Zappa attempted to earn a living as a musician and Composer, and played different nightclub gigs, some with a new version of the Blackouts. Zappa's earliest professional recordings, two soundtracks for the low-budget films The World's Greatest Sinner (1962) and Run Home Slow (1965) were more financially rewarding. The former score was commissioned by actor-producer Timothy Carey and recorded in 1961. It contains many themes that appeared on later Zappa records. The latter Soundtrack was recorded in 1963 after the film was completed, but it was commissioned by one of Zappa's former high school teachers in 1959 and Zappa may have worked on it before the film was shot. Excerpts from the Soundtrack can be heard on the posthumous album The Lost Episodes (1996).

In 1964, after his marriage started to break up, he moved into the Pal studio and began routinely working 12 hours or more per day recording and experimenting with overdubbing and audio tape manipulation. This established a work pattern that endured for most of his life. Aided by his income from film composing, Zappa took over the studio from Paul Buff, who was now working with Art Laboe at Original Sound. It was renamed Studio Z. Studio Z was rarely booked for recordings by other Musicians. Instead, friends moved in, notably James "Motorhead" Sherwood. Zappa started performing in local bars as a Guitarist with a power trio, the Muthers, to support himself.

In 1965, Ray Collins asked Zappa to take over as Guitarist in local R&B band the Soul Giants, following a fight between Collins and the group's original Guitarist. Zappa accepted, and soon assumed leadership and the role as co-lead singer (even though he never considered himself a singer). He convinced the other members that they should play his music to increase the chances of getting a record contract. The band was renamed the Mothers, coincidentally on Mother's Day. They increased their bookings after beginning an association with manager Herb Cohen, while they gradually gained attention on the burgeoning Los Angeles underground music scene. In early 1966, they were spotted by leading record Producer Tom Wilson when playing "Trouble Every Day", a song about the Watts riots. Wilson had earned acclaim as the Producer for Bob Dylan and Simon & Garfunkel, and was notable as one of the few African-Americans working as a major label pop music Producer at this time. Wilson signed the Mothers to the Verve division of MGM, which had built up a strong reputation for its releases of modern jazz recordings in the 1940s and 1950s, but was attempting to diversify into pop and rock audiences. Verve insisted that the band officially rename themselves the Mothers of Invention as Mother was short for motherfucker—a term that, apart from its profane meanings, can denote a skilled musician.

The Mothers of Invention played in New York in late 1966 and were offered a contract at the Garrick Theater (at 152 Bleecker Street, above the Cafe au Go Go) during Easter 1967. This proved successful and Herb Cohen extended the booking, which eventually lasted half a year. As a result, Zappa and his wife, along with the Mothers of Invention, moved to New York. Their shows became a combination of improvised acts showcasing individual talents of the band as well as tight performances of Zappa's music. Everything was directed by Zappa using hand signals. Guest performers and audience participation became a regular part of the Garrick Theater shows. One evening, Zappa managed to entice some U.S. Marines from the audience onto the stage, where they proceeded to dismember a big baby doll, having been told by Zappa to pretend that it was a "gook baby".

Scientists from various fields have honored Zappa by naming new discoveries after him. In 1967, Paleontologist Leo P. Plas, Jr. identified an extinct mollusc in Nevada and named it Amaurotoma zappa with the motivation that, "The specific name, zappa, honors Frank Zappa".

Zappa and the Mothers of Invention returned to Los Angeles in mid-1968, and the Zappas moved into a house on Laurel Canyon Boulevard, only to move again to one on Woodrow Wilson Drive. This was Zappa's home for the rest of his life. Despite being a success with fans in Europe, the Mothers of Invention were not faring well financially. Their first records were vocally oriented, but Zappa wrote more instrumental jazz and classical oriented music for the band's concerts, which confused audiences. Zappa felt that audiences failed to appreciate his "electrical chamber music".

In New York, Zappa increasingly used tape editing as a compositional tool. A prime Example is found on the double album Uncle Meat (1969), where the track "King Kong" is edited from various studio and live performances. Zappa had begun regularly recording concerts, and because of his insistence on precise tuning and timing, he was able to augment his studio productions with excerpts from live shows, and vice versa. Later, he combined recordings of different compositions into new pieces, irrespective of the tempo or meter of the sources. He dubbed this process "xenochrony" (strange synchronizations)—reflecting the Greek "xeno" (alien or strange) and "chronos" (time).

Resolving the lawsuits successfully, Zappa ended the 1970s "stronger than ever", by releasing two of his most successful albums in 1979: the best selling album of his career, Sheik Yerbouti, and in Kelley Lowe's opinion the "bona fide masterpiece", Joe's Garage.

In 1971, biographer David Walley noted that "The whole structure of his music is unified, not neatly divided by dates or time sequences and it is all building into a composite". On commenting on Zappa's music, politics and philosophy, Barry Miles noted in 2004 that they cannot be separated: "It was all one; all part of his 'conceptual continuity'."

This attack resulted in an extended period of wheelchair confinement, making touring impossible for over half a year. Upon return to the stage in September 1972, Zappa was still wearing a leg brace, had a noticeable limp and could not stand for very long while on stage. Zappa noted that one leg healed "shorter than the other" (a reference later found in the lyrics of songs "Zomby Woof" and "Dancin' Fool"), resulting in chronic back pain. Meanwhile, the Mothers were left in limbo and eventually formed the core of Flo and Eddie's band as they set out on their own.

By 1973 the Bizarre and Straight labels were discontinued. In their place, Zappa and Cohen created DiscReet Records, also distributed by Warner Bros. Zappa continued a high rate of production through the first half of the 1970s, including the solo album Apostrophe (') (1974), which reached a career-high No. 10 on the Billboard pop album charts helped by the No. 86 chart hit "Don't Eat The Yellow Snow". Other albums from the period are Over-Nite Sensation (1973), which contained several Future concert favorites, such as "Dinah-Moe Humm" and "Montana", and the albums Roxy & Elsewhere (1974) and One Size Fits All (1975) which feature ever-changing versions of a band still called the Mothers, and are notable for the tight renditions of highly difficult jazz fusion songs in such pieces as "Inca Roads", "Echidna's Arf (Of You)" and "Be-Bop Tango (Of the Old Jazzmen's Church)". A live recording from 1974, You Can't Do That on Stage Anymore, Vol. 2 (1988), captures "the full spirit and excellence of the 1973–75 band". Zappa released Bongo Fury (1975), which featured a live recording at the Armadillo World Headquarters in Austin from a tour the same year that reunited him with Captain Beefheart for a brief period. They later became estranged for a period of years, but were in contact at the end of Zappa's life.

Although Zappa eventually gained the rights to all his material created under the MGM and Warner Bros. contracts, the various lawsuits meant that for a period Zappa's only income came from touring, which he therefore did extensively in 1975–77 with relatively small, mainly rock-oriented, bands. Drummer Terry Bozzio became a regular band member, Napoleon Murphy Brock stayed on for a while, and original Mothers of Invention Bassist Roy Estrada joined. Among other Musicians were Bassist Patrick O'Hearn, singer-guitarist Ray White and keyboardist/violinist Eddie Jobson. In December 1976, Zappa appeared as a featured musical guest on the NBC television show Saturday Night Live. Zappa's song "I'm the Slime" was performed with a voice-over by SNL booth announcer Don Pardo, who also introduced "Peaches En Regalia" on the same airing. In 1978, Zappa served both as host and musical act on the show, and as an actor in various sketches. The performances included an impromptu musical collaboration with cast member John Belushi during the instrumental piece "The Purple Lagoon". Belushi appeared as his Samurai Futaba character playing the tenor sax with Zappa conducting.

Zappa's relationship with long-time manager Herb Cohen ended in 1976. Zappa sued Cohen for skimming more than he was allocated from DiscReet Records, as well as for signing acts of which Zappa did not approve. Cohen filed a lawsuit against Zappa in return, which froze the money Zappa and Cohen had gained from an out-of-court settlement with MGM over the rights of the early Mothers of Invention recordings. It also prevented Zappa having access to any of his previously recorded material during the trials. Zappa therefore took his personal master copies of the rock-oriented Zoot Allures (1976) directly to Warner Bros., thereby bypassing DiscReet.

Zappa in New York featured a song about sex Criminal Michael H. Kenyon, "The Illinois Enema Bandit", which featured Don Pardo providing the opening narrative in the song. Like many songs on the album, it contained numerous sexual references, leading to many critics objecting and being offended by the content. Zappa dismissed the criticism by noting that he was a Journalist reporting on life as he saw it. Predating his later fight against censorship, he remarked: "What do you make of a society that is so primitive that it clings to the belief that certain words in its language are so powerful that they could corrupt you the moment you hear them?" The remaining albums released by Warner Bros. Records without Zappa's consent were Studio Tan in 1978 and Sleep Dirt and Orchestral Favorites in 1979, which contained complex suites of instrumentally-based tunes recorded between 1973 and 1976, and whose release was overlooked in the midst of the legal problems.

The albums focus exclusively on Frank Zappa as a guitar soloist, and the tracks are predominantly live recordings from 1979 to 1980; they highlight Zappa's improvisational skills with "beautiful performances from the backing group as well". Another guitar-only album, Guitar, was released in 1988, and a third, Trance-Fusion, which Zappa completed shortly before his death, was released in 2006.

Belgian biologists Bosmans and Bosselaers discovered in the early 1980s a Cameroonese spider, which they in 1994 named Pachygnatha zappa because "the ventral side of the abdomen of the female of this species strikingly resembles the artist's legendary moustache".

In 1981, Zappa also released three instrumental albums, Shut Up 'n Play Yer Guitar, Shut Up 'N Play Yer Guitar Some More, and The Return of the Son of Shut Up 'N Play Yer Guitar, which were initially sold via mail order, but later released through the CBS label due to popular demand.

In May 1982, Zappa released Ship Arriving Too Late to Save a Drowning Witch, which featured his biggest selling single ever, the Grammy Award-nominated song "Valley Girl" (topping out at No. 32 on the Billboard charts). In her improvised lyrics to the song, Zappa's daughter Moon Unit satirized the patois of teenage girls from the San Fernando Valley, which popularized many "Valspeak" expressions such as "gag me with a spoon", "fer sure, fer sure", "grody to the max", and "barf out".

Zappa is widely recognized as one of the most significant electric guitar soloists. In a 1983 issue of Guitar World, Jon Swenson declared: "the fact of the matter is that [Zappa] is one of the greatest guitarists we have and is sorely unappreciated as such." His idiosyncratic style developed gradually and was mature by the early 1980s, by which time his live performances featured lengthy improvised solos during many songs. A November 2016 feature by the editors of Guitar Player magazine wrote: "Brimming with sophisticated motifs and convoluted rhythms, Zappa's extended excursions are more akin to symphonies than they are to guitar solos." The symphonic comparison stems from his habit of introducing melodic themes that, like a symphony's main melodies, were repeated with variations throughout his solos. He was further described as using a wide variety of scales and modes, enlivened by "unusual rhythmic combinations". His left hand was capable of smooth legato technique, while Zappa's right was "one of the fastest pick hands in the Business."

Francesco Zappa, a Synclavier rendition of works by 18th-century Composer Francesco Zappa was also released in 1984.

Zappa set excerpts from the PMRC hearings to Synclavier music in his composition "Porn Wars" on the 1985 album Frank Zappa Meets the Mothers of Prevention, and the full recording was released in 2010 as Congress Shall Make No Law... Zappa is heard interacting with Senators Fritz Hollings, Slade Gorton and Al Gore.

The album Jazz from Hell, released in 1986, earned Zappa his first Grammy Award in 1988 for Best Rock Instrumental Performance. Except for one live guitar solo ("St. Etienne"), the album exclusively featured compositions brought to life by the Synclavier. Although an instrumental album, containing no lyrics, Meyer Music Markets sold Jazz from Hell featuring an "explicit lyrics" sticker—a warning label introduced by the Recording Industry Association of America in an agreement with the Parents Music Resource Center (PMRC).

Zappa's last tour in a rock and jazz band format took place in 1988 with a 12-piece group which had a repertoire of over 100 (mostly Zappa) compositions, but which split under acrimonious circumstances before the tour was completed. The tour was documented on the albums Broadway the Hard Way (new material featuring songs with strong political emphasis); The Best Band You Never Heard in Your Life (Zappa "standards" and an eclectic collection of cover tunes, ranging from Maurice Ravel's Boléro to Led Zeppelin's Stairway to Heaven); and Make a Jazz Noise Here. Parts are also found on You Can't Do That on Stage Anymore, volumes 4 and 6. Recordings from this tour also appear on the 2006 album Trance-Fusion.

In the late 1990s, American paleontologists Marc Salak and Halard L. Lescinsky discovered a metazoan fossil, and named it Spygori zappania to honor "the late Frank Zappa ... whose mission paralleled that of the earliest paleontologists: to challenge conventional and traditional beliefs when such beliefs lacked roots in logic and reason".

In a 1991 interview, Zappa reported that he was a registered Democrat but added "that might not last long—I'm going to shred that". Describing his political views, Zappa categorized himself as a "practical conservative". He favored limited government and low taxes; he also stated that he approved of national defense, social security, and other federal programs, but only if recipients of such programs are willing and able to pay for them. He favored capitalism, entrepreneurship, and independent Business, stating that Musicians could make more from owning their own businesses than from collecting royalties. He opposed communism, stating, "A system that doesn't allow ownership ... has—to put it mildly—a fatal design flaw." He had always encouraged his fans to register to vote on album covers, and throughout 1988 he had registration booths at his concerts. He even considered running for President of the United States as an independent.

Guitar Player devoted a special issue to Zappa in 1992, and asked on the cover "Is FZ America's Best Kept Musical Secret?" Editor Don Menn remarked that the issue was about "The most important Composer to come out of modern popular music".

Zappa died, after his long battle with prostate cancer, on December 4, 1993, just 18 days before his 53rd birthday at his home with his wife and children by his side. At a private ceremony the following day, his body was buried in a grave at the Westwood Village Memorial Park Cemetery, in Los Angeles. The grave is unmarked. On December 6, his family publicly announced that "Composer Frank Zappa left for his final tour just before 6:00 pm on Saturday".

During his lifetime, Zappa released 62 albums. Since 1994, the Zappa Family Trust has released 49 posthumous albums, making a total of 111 albums. The current distributor of Zappa's recorded output is Universal Music Enterprises. Frank Zappa has sold more than 40 million records worldwide.

A gene of the bacterium Proteus mirabilis that causes urinary tract infections was in 1995 named zapA by three biologists from Maryland. In their scientific article, they "especially thank the late Frank Zappa for inspiration and assistance with genetic nomenclature". Repeating regions of the genome of the human tumor virus KSHV were named frnk, vnct and zppa in 1996 by the Moore and Chang who discovered the virus. Also, a 143 base pair repeat sequence occurring at two positions was named waka/jwka.

In 2002, a bronze bust was installed in German city Bad Doberan, location of the Zappanale since 1990, an annual music festival celebrating Zappa. At the initiative of Musicians community ORWOhaus, the city of Berlin named a street in the Marzahn district "Frank-Zappa-Straße" in 2007. The same year, Baltimore mayor Sheila Dixon proclaimed August 9 as the city's official "Frank Zappa Day" citing Zappa's musical accomplishments as well as his defense of the First Amendment to the United States Constitution.

Zappa earned widespread critical acclaim in his lifetime and after his death. The Rolling Stone Album Guide (2004) writes: "Frank Zappa dabbled in virtually all kinds of music—and, whether guised as a satirical rocker, jazz-rock fusionist, guitar virtuoso, electronics wizard, or orchestral innovator, his eccentric genius was undeniable." Even though his work drew inspiration from many different genres, Zappa was seen as establishing a coherent and personal expression.

In 2005, the U.S. National Recording Preservation Board included We're Only in It for the Money in the National Recording Registry as "Frank Zappa's inventive and iconoclastic album presents a unique political stance, both anti-conservative and anti-counterculture, and features a scathing satire on hippiedom and America's reactions to it". The same year, Rolling Stone magazine ranked him at No. 71 on its list of the 100 Greatest Artists of All Time.

In 1994, lobbying efforts initiated by Psychiatrist John Scialli led the International Astronomical Union's Minor Planet Center to name an asteroid in Zappa's honor: 3834 Zappafrank. The asteroid was discovered in 1980 by Czechoslovakian Astronomer Ladislav Brožek, and the citation for its naming says that "Zappa was an eclectic, self-trained Artist and composer ... Before 1989 he was regarded as a symbol of democracy and freedom by many people in Czechoslovakia". In 1995, a bust of Zappa by Sculptor Konstantinas Bogdanas was installed in Vilnius, the Lithuanian capital (54.683, 25.2759). The choice of Zappa was explained as "a symbol that would mark the end of communism, but at the same time express that it wasn't always doom and gloom." A replica was offered to the city of Baltimore in 2008, and on September 19, 2010 — the twenty-fifth anniversary of Zappa's testimony to the U.S. Senate — a ceremony dedicating the replica was held, and the bust was unveiled at a library in the city.

In 2011, he was ranked at No. 22 on the list of the 100 Greatest Guitarists of All Time by the same magazine.

After 200 Motels, the band went on tour, which resulted in two live albums, Fillmore East – June 1971 and Just Another Band from L.A.; the latter included the 20-minute track "Billy the Mountain", Zappa's satire on rock opera set in Southern California. This track was representative of the band's theatrical performances—which used songs to build sketches based on 200 Motels scenes, as well as new situations that often portrayed the band members' sexual encounters on the road.

While he disapproved of drug use, he criticized the War on Drugs, comparing it to alcohol prohibition, and stated that the United States Treasury would benefit from the decriminalization and regulation of drugs. Describing his philosophical views, Zappa stated, "I believe that people have a right to decide their own destinies; people own themselves. I also believe that, in a democracy, government exists because (and only so long as) individual citizens give it a 'temporary license to exist'—in exchange for a promise that it will behave itself. In a democracy, you own the government—it doesn't own you."

Following Zappa's death, his widow Gail created the Zappa Family Trust, which owns the rights to a massive trove of music and other creative output: more than 60 albums were released during Zappa's lifetime and 40 posthumously that are potentially worth at least tens of millions of dollars. Upon Gail's death in October 2015, it was revealed that Zappa's youngest children, Ahmet and Diva, were given control of the trust with shares of 30% each, while his older children Moon and Dweezil were given smaller shares of 20% each. As beneficiaries only, Moon and Dweezil will not see any money from the trust until it is profitable—in 2016, it was "millions of dollars in debt"—and must seek permission from Ahmet, the trustee, to make money off their father's music or merchandise bearing his name. The uneven divide of the trust has resulted in several conflicts between Zappa's children, including a feud between Dweezil and Ahmet over Dweezil's use of his father's music in live performances.