Kirstie Alley - first TV appearance - Match Game 1979

Her breakout 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, she starred as the lead in the sitcom Veronica's Closet, earning additional Emmy and Golden Globe nominations. On film, she played Mollie Jensen in Look Who's Talking (1989) and its two sequels, Look Who's Talking Too (1990) and Look Who's Talking Now (1993).

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).

Alley won her second Emmy Award in 1994 for the television film David's Mother. In 1997, Alley received another Emmy nomination for her work in the crime drama series The Last Don. In 2005, she 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 2013, Alley returned to acting with the title role on the sitcom Kirstie. In 2016, she appeared on the Fox comedy horror series Scream Queens.

She also appeared in reality television including Kirstie Alley's Big Life (2010) and served as a contestant on the 12th season of Dancing with the Stars (2011–2012), where she finished in second place, behind Hines Ward, and the 22nd series of the British reality show Celebrity Big Brother (2018), in which she finished as runner-up. In early 2022, she appeared on The Masked Singer.