John "The Colonel" Camden (Peter Graves) is Eric, Julie, and George's father, who used to be in the Marines. Whenever he visits his son's home to visit the grandchildren, he expects military discipline, order and organization, even from his son. He was a Colonel in the Korean War and was evacuated for an unknown reason in 1953. He met Ruth the same year and they were expecting Eric and had to get married. He first appears in "Seven Is Enough", when he and Ruth go on their annual visit to the Camdens, where they always bring candy that their grandkids dislike. During their visit, they go to a hardware store with Annie, Mary, and Lucy. The cashier, Emma, has rings that are a replica of Annie's stolen ones. She suspects this, but then excuses this thought. The Colonel visits Eric at the church and is forced to put a cigar away because of a church rule. He suspects someone is in the room, and sure enough, a homeless orphan named George was hiding there. The Colonel and Ruth adopt him after Eric lets them. He later appears in "It's About George", where George's biological father Will Grayson is found to be alive and wants his son back. He does not want this to happen, so he is willing to sue. Eric informs his father that he would lose and that Will legally has every right to take George with him, but George refuses to move in with Will and runs away. Eric later creates a compromise and he reluctantly accepts. He also meets Jimmy Moon in this episode, where he and Ruth scare him, but later apologize. He thought that Julie hated him and that he lost all of his children. Julie later confronts him and tells him that she loves him. He and Ruth buy Eric an RV the final episode, though he is not shown.

Rev. Eric Camden (played by Stephen Collins) was raised in Binghamton, New York by his parents, Colonel John Camden and Ruth Lynch. Based on the episode "Halloween" (season 1), it appears that Eric was born in 1954 (which would make him 42 years old at the time). According to the episode "One Hundred" (season 5), his birthday is in January. Eric attended college for five years and graduated from Cobell Seminary. Shortly thereafter, he married and began a family with Annie Jackson. He has one sister, Julie Camden-Hastings, who ends up marrying the Doctor that delivered Eric and Annie's oldest (Matt), as well as the youngest (Sam and David) children. After his heart-bypass operation, he decides to leave the ministry and even stop attending church. He renews his faith and returns to church in time to marry Kevin and Lucy (near the end of season 7).

Matthew "Matt" Camden (played by Barry Watson) (born 1980) is Annie and Eric's firstborn. In the beginning of the series, Matt is a junior in high school. Matt sacrifices his school time to help others; if they wished to remain anonymous, he would respect that and not even tell his father. During high school, he bounces from job to job, including tutor and Dairy Shack delivery driver. He is not always a star student, but he manages to graduate at the top of his class and get accepted for a White House internship in Washington, D.C. with First Lady Hillary Clinton. He returns to Glenoak for college, rooming with friend and fellow "P.K." John Hamilton. Matt's new uncle, Dr. Hank Hastings (who had actually delivered him), helps him get a job in the hospital cafeteria; during his time there, he decides to become a Doctor. He ends up working at a women's clinic with Hank, beginning by helping save the life of a woman who could not get anyone but Matt to take her symptoms of an ectopic pregnancy seriously.

Mary Camden (played by Jessica Biel) (born 1982) is the eldest daughter of Eric and Annie. By the time she is 14, Mary is an aspiring athlete with an immense love for basketball. As the months progress, she seems to rise in both ability and confidence (so much so that she wants to play in the WNBA someday) until she is hit by a car before the end of her freshman year, critically injuring her knee. She has a series of different boyfriends. She dates Wilson West, a guy she meets at the park while with Ruthie, who becomes her first love. He later reveals to Mary that he had sex with a sixteen-year-old girl, and got her pregnant. The girl died in childbirth, leaving Wilson with a son, Billy (actually named Wilson Jr.). By her senior year, she and her basketball teammates allow their grades to slip, which causes their coach to impose a lockout on them. After a secret meeting, the team decides to enact their frustrations by vandalizing the school gym. They are caught at the scene of the crime, and are arrested. Through a special program for first offenders, Mary is able to evade serious punishment by doing community Service, which is where she meets Robbie Palmer. When she gets her driver's license, she can't parallel park but, on Lucy's advice, cries about it and the driving instructor compassionately gives her a passing grade. Mary has a dream of playing pro for the Lakers, and thinks that when her coach rings her up that this is the dream coming true, but it's actually training disabled people for the Special Olympics.

Lucy Camden-Kinkirk (played by Beverley Mitchell) (born 1983) is the third Camden child, and second daughter. Lucy is known (in the earlier seasons) for the many boyfriends she has, as well as being overly dramatic. Until season 4, she is often seen as "less than" her sister Mary and her emotions often get her into trouble. By the time she reaches her junior year in high school, however, Lucy becomes much more settled and switches positions with Mary, becoming the good kid. Her first boyfriend is Jimmy Moon. She has one "normal" relationship with him, but they break up. In the beginning of season two, she is crying all summer and says that Jimmy is dating Ashley. At one point, she gets arrested for being in the area where Jimmy is dealing drugs. Later, Jimmy is shown when he had some problems with drugs, and the last time is when Lucy had a case as juror (though nobody told her what it was about; because she knew the defendant personally, she was dismissed). In school, she has lots of friends and is popular—including being nominated for homecoming queen in her senior year. She has a very good relationship with her friend Mike, who is placed in a mental hospital and is otherwise ostracized. Although Mike likes Lucy, it never quite works out. Later Lucy becomes engaged to Mike's friend, Jeremy, but they eventually break it off.

Simon Camden (played by David Gallagher) (born 1986) is the fourth child and second son. In the early part of the series, he is known to his siblings as "The Bank of Simon" because he always seems to have money, and he loves to make money. His other interests have included golf, magic, and cars.

Ruth "Ruthie" Camden (played by Mackenzie Rosman) (born 1991) is the youngest daughter. She is named in honor of her paternal grandmother.

John Hamilton (1996–2001) (Chaz Lamar Shepherd) is the oldest of the Hamilton children. He first appears in "The Color of God." When his father's church is burned down, he stays in Matt's room. At first, the two are not very fond of each other, but this later changes. He later appears in the episode "America's Most Wanted" where he is an eyewitness to Mary stealing a glass from a restaurant as part of a team ritual. He appears in "Happy's Valentine", where he brings a date to the Camdens' while his parents and Eric and Annie are out of town, joining the wild party that Mary and Keesha's friends are throwing. He later becomes Matt's roommate. He later married to a woman named Priscilla Carter at the end of season five, his last appearance on the show.

Shana Sullivan (1998–2002) (Maureen Flannigan) is one of Matt's major girlfriends, who eventually decides to go to New York University. The resulting long-distance relationship between Matt and Shana fails. Shana and Matt eventually break up because Shana meets somebody else named Brett and Matt admits that he is in love with Heather.

Robbie Palmer (1999–2002) (Adam LaVorgna) is Mary's, and then later Lucy's, boyfriend. He had been with some friends who were drinking underage and they were all arrested. Being a first time offender, he is able to avoid serious punishment by doing community Service. While doing community Service, he meets Mary. The two have dates at the Camden house under Eric and Annie’s supervision, because they feel they cannot trust Robbie. After a while, Robbie convinces Eric and Annie to let him take Mary to the coffee shop, where his parents met, for Valentine’s Day. The coffee shop turns out to be a motel. Mary punches him and leaves. He comes back a few months later to try to win back Mary. The two get back together, get engaged, and plan to move in together. However, Robbie’s ex-girlfriend, Cheryl, sees him and Mary together and realizes that he had been two-timing her. She tells Mary and Mary breaks up with him because she needs to figure out her life.

Cecilia Smith (2002–2004) (Ashlee Simpson) is Simon's girlfriend, who then dates Martin. She later dumps Martin, who loved her but she was not sure she felt the same. Another reason (which is not very clearly shown) might be that she thought Simon was returning—whereas he only came for vacations—and they might get back together (because it would no longer be a long-distance relationship). When Simon comes home (at the end of season eight), it was vaguely revealed that their relationship did not work out, because over the summer Cecilia went away to college, and it was only when Simon begins dating and having sex with Georgia (in season nine) that it is revealed that they had broken up.

Martin Brewer (2003–2007) (Tyler Hoechlin) is the only son of the Marine, Bill Brewer. His mother died when he was young and, until he was 16, he lived with his Aunt Betsy, when his dad was deployed. During his sophomore year in high school, the Brewers moved to Glenoak.

Meredith Davies (2004–2005) (Megan Henning) is Martin's ex-girlfriend, who ends their relationship after he told her about Sandy and the baby. Meredith and her siblings were taken in by Cecilia's parents, but were never legally adopted by them due to the meddling of their birth mother. After she and Martin breakup, Meredith's younger sister tells everyone at school that Martin got Ruthie pregnant. After discovering this, Meredith quickly denies the rumor, explaining to her sister that Martin got Sandy pregnant.

Rosanna "Rose" Taylor (2005–2006) (Sarah Thompson) was introduced (in the season nine finale "Mi Familia Part 1") as Simon's current girlfriend. The two are not necessarily serious but she seems eager to engage and marry, pressuring Simon into proposing. When at first he refuses, she takes it as disinterest in her and backs away, provoking him to commit to marrying her. By season ten they are engaged, and she makes wedding plans. The initial plan was for the two to engage at the end of their current school year and wed at the end of the following year, but she pressures him into moving the engagement date forward. During Rose's time on the show, she becomes a very disliked person by all except for Sandy Jameson, who was her one friend there. Rose is known for being selfish, rude, inconsiderate, and thoughtless, rubbing Eric and Annie the wrong way more than anyone.

By 2006, Simon and Rose change plans to marry in May, something they both wanted to be ready for, but still held insecurities and doubts. Annie, however, decides that they could not marry, and when an ex-boyfriend of Rose's surfaces in March, she sees an opportunity. Though most had come to accept Simon dating Rose, no one knew her at all, and it was this boyfriend who convinces Rose that she is not being a good person. In the episode Invitation to Disaster, she has a sit-down confession with Annie, explaining that she has been unaware of how she was acting and that her relationship with her parents and never really being disciplined or close to them at all is part of the reason. This provokes Annie to see her in a different light, and while she and Annie take on a mother/daughter relationship, no one else is crazy about them marrying. It is her ex-boyfriend Humberto who makes her realize that she is not ready to marry and that he still has feelings for her. So although they had gotten to the wedding day, they end up parting ways amicably. It is unknown whether they still keep in touch.

In 2009, she was included in Yahoo!'s Top 10 TV Moms from Six Decades of Television for the decade 1996–2007.

Ruthie is the only one to briefly attend a private school, but she leaves it in protest that her friend Yasmine is being denied admission because she is a Muslim. During her freshman year she develops feelings for Camden houseguest Martin Brewer and even tells him she loves him—but quickly covers by adding "as a brother." In her sophomore year of high school she begins to wear makeup and dates older boys in the hope that this would lead to a relationship with Martin. In season ten's "Love and Obsession", she dreams everything from Martin telling her that a paternity test had proved that Simon, not Martin, is Aaron's father; to there being no Aaron at all because Martin had never met Sandy. When her former boyfriend and first love Peter returns during this time, she realizes that she had moved on from him. After ignoring Sandy for most of her pregnancy, Martin is present for Aaron's birth, as are both of Aaron's grandfathers-to-be. Upon Aaron's birth Martin leaves Glenoak for college; he now lives near his son. This leaves Ruthie heartbroken, but by the time Martin finally admits to her that he loves her, she is in love with new Camden houseguest T-Bone. Ruthie and T-Bone love each other very much and even get tattoos of each other's names. Well Ruthie gets T-Bone name but T-Bone was scared of the needle so he just got Ruthies initials R.C. After an argument they break up. Ruthie starts seeing Martin briefly. Martin says he wants to work things out with her but Ruthie chooses T-Bone and then Ruthie and T-Bone get back together. Ruthie decides to graduate from high school early and that he and T-Bone wan a travel the world together. After her graduation, Ruthie with T-Bone join the whole family, and the other current Camden house guests, for an RV road trip that includes a stop at Simon's college graduation and that after that Ruthie and T-Bone plain to go travel the world together.

Robbie comes back a few months later with Cheryl, asking if Eric would marry the two of them because she was pregnant, which is not true, and the two are living together in Cheryl’s apartment. Eric later finds Robbie living on the streets, and Robbie tells him that the only reason he was going to marry Cheryl was because she was pregnant, and when he found out she wasn’t, he left, but had nowhere to go. Eric invites Robbie to stay in the Camden house, which does not go over very well with the rest of the family. But in time, everyone came to treat Robbie like a member of the family. He and Mary started dating again and she planned to come home from New York for the summer to be with him. However, her old boyfriend, Wilson West, comes to beg Mary to stay in New York with him. She chooses to be with Wilson, and leaves Robbie heartbroken.