Her breakthrough role was as Rebecca Howe in the NBC sitcom Cheers (1987–1993), for which she received an Emmy Award and a Golden Globe in 1991.

From 1997 to 2000, Alley starred as the lead in the sitcom Veronica's Closet, earning additional Emmy and Golden Globe nominations.

Throughout the 1980s and 1990s, Alley appeared in various films, including Star Trek II: The Wrath of Khan (1982), Summer School (1987), Shoot to Kill (1988), Madhouse (1990), Sibling Rivalry (1990), Village of the Damned (1995), It Takes Two (1995), Deconstructing Harry (1997), For Richer or Poorer (1997), and Drop Dead Gorgeous (1999).

In 2005, Alley played a fictionalized version of herself on Showtime's Fat Actress, something she would also do on episodes of King of Queens and Hot in Cleveland, as well as in Syrup (2013).

In 1981, an automobile crash involving a drunk driver[3] killed Alley's mother and left her father seriously injured.

[2] In 1982, Alley made her film debut in Star Trek II: The Wrath of Khan in the role of the Vulcan Starfleet officer Lieutenant Saavik.

In 1985, she starred in the ABC miniseries North and South,[9] and also portrayed feminist icon Gloria Steinem in the television movie A Bunny's Tale.

Alley remained with the show for six years until its eleventh and final season,[11] and earned an Emmy Award and Golden Globe.

[15] Her later films included Village of the Damned (1995), It Takes Two (1995), Deconstructing Harry (1997), For Richer or Poorer (1997), and Drop Dead Gorgeous (1999).

From 1997 to 2000, Alley played the title character and was executive producer in the NBC sitcom Veronica's Closet, where she earned another Emmy and Golden Globe nomination.

[17][18] Beginning in December 2013, TV Land aired a sitcom that centered on Alley as Broadway star Madison "Maddie" Banks, who reconnects with her adult son who she gave up for adoption shortly after he was born.

The series was titled Kirstie, and reunited her with former Cheers co-star Rhea Perlman and Seinfeld star Michael Richards.

[25] In 1988 and 2000 respectively, Alley purchased estates in Jacksonville, Oregon, and Clearwater, Florida, retaining ownership of both properties until her death in 2022.

[31] In March 2010, after gossip blogger Roger Friedman alleged a link between her Organic Liaison weight-loss system and the Church of Scientology, Alley denied it on the Today show.

[32] In September 2011, Alley announced that she had lost 100 lb (45 kg) using weight loss products from Organic Liaison.

[33] In 2012, Alley faced a class-action lawsuit alleging false advertising; the suit claimed that her weight loss was the result of exercise, including training for the TV show Dancing with the Stars, not Organic Liaison products.

[44] Alley said she supported both Democratic and Republican presidential nominees and independent Ross Perot in 1992, but decided not to vote in 1988 and 2004.

[52][53][54][55] Alley's ex-husband Parker Stevenson, her two children, her Look Who's Talking co-star John Travolta,[56] and other celebrities posted their condolences on social media.