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Perlman received ten Emmy Award nominations for Best Supporting Actress in a Comedy Series (Cheers ran 11 seasons, from 19821993; the only year in which Perlman wasn't nominated was 1992). She won the Emmy four times, in 1984, 1985, 1986 and 1989. She later starred in the 1996 sitcom Pearl as the title character and was featured on the 2001 TV drama Kate Brasher. She also appeared in a 2000 television film How to Marry a Billionaire: A Christmas Tale, in which she played Jacqueline Kennedy.
Perlman had a recurring role on the television show "Taxi" as Zena, Louis DePalma's (Danny DeVito) girlfriend. Perlman also played the role of Honey in the film Canadian Bacon and she appeared in the movie Matilda opposite her husband Danny DeVito, Pam Ferris and Mara Wilson. She also played the grumpy shopkeeper in "Packin It In".