Wretzky is the credited Bassist on the Smashing Pumpkins' first five studio albums: Gish, Siamese Dream, Mellon Collie and the Infinite Sadness, Adore, and Machina/The Machines of God. It was confirmed by both her and Corgan, however, that Corgan played the bass tracks for Siamese Dream because he could complete them in far fewer takes. Wretzky often contributed backing vocals in concert, and on studio albums. She contributes vocally in some Smashing Pumpkins songs including "Daydream" from Gish, many songs on Siamese Dream, "1979", "Cupid De Locke", "Farewell and Goodnight", "Beautiful"; "Where Boys Fear To Tread" from Mellon Collie, and "Dreaming" and "The Bells" from The Aeroplane Flies High. Wretzky also co-wrote one Smashing Pumpkins song, "Daughter".

Wretzky's time in the band was marked by alternating periods of happiness and discomfort. Corgan considered her the "moral authority" and "moral conscience" of the band. In the aftermath of the success of 1995's Mellon Collie and the Infinite Sadness, Corgan said she began an "apparent slow descent into insanity and/or drugs (take your pick)." After the short, nine-date "The Arising!" tour in April 1999 which saw all four original members performing together for the first time since 1996, Wretzky decided to leave the band with intentions of pursuing an acting career. The band was recording Machina/The Machines of God at the time and consequently she performed very few bass parts on the album. Most of the bass parts were handled by Corgan himself. Shortly after leaving the group, she was arrested for possession of crack cocaine. Corgan later said she was "fired for being a mean-spirited drug addict who refused to get help." She was replaced on 2000s Machina tour by former Hole Bassist Melissa Auf der Maur.

Wretzky contributed vocals to the track "One and Two" on James Iha's 1998 solo album, Let It Come Down.

In 1999, she contributed vocals on a Filter song, "Cancer". During this time, she worked with Cellist Eric Remschneider, whom she had worked with when he had recorded with the Smashing Pumpkins.

Wretzky did not participate in the Smashing Pumpkins' reunion. In 2008, she and her former bandmate James Iha filed a lawsuit against Virgin Records for selling ringtones of Smashing Pumpkins songs without their consent.

After many years out of the spotlight, Wretzky resurfaced in July 2009 by calling in unexpectedly on Chicago's Q101 FM with Ryan Manno. During the interview, she stated that she was not healthy enough to be a musician, and repeatedly professed her admiration for Monkees frontman Davy Jones who was known to be an early romantic crush of Wretzky's. She also discussed her appreciation for the band Silversun Pickups who have a sound influenced by the early Gish era of the Smashing Pumpkins. She also mentioned that she then lived on a farm in Michigan, that she had briefly lived in Austin, Texas, sometime during the previous decade, and that former fiancé Wendell Green had died.

Wretzky was jailed in February 2011 for missing four court dates related to a ticket she received for failing to control her horses. She spent six days in jail. She was also arrested on February 7, 2011, on a misdemeanor drunken-driving charge in South Haven, Michigan.

In 2013, Wretzky's relationship with Corgan remained tense. In September 2014, she tried to re-establish contact with him.

In May 2016 in an interview with Loudwire, Filter lead singer Richard Patrick spoke of a romantic relationship he had with Wretzky saying she was the subject of a song he wrote called "Miss Blue"

On February 14, 2018, Wretzky gave her first interview in nearly 20 years. In it she is highly critical of Corgan and their past.