Tomei appeared in the original cast of several pioneering Off-Broadway productions, including Caryl Churchill's Cloud Nine and Larry Kramer's The Normal Heart. She appeared opposite Kevin Kline in the New York Shakespeare Festival's Richard III (winning New York's Bayfield Shakespearean award for her performance) and starred with David Bowie in the Broadway production of The Elephant Man, continuing in the national tour.
In the 1980s, she moved to California and appeared in many regional theatres, including Los Angeles' Mark Taper Forum, the Oregon Contemporary Theatre, and San Francisco's ACT. She was a regular cast member in the TV-series China Beach, which ran from 1988–1991. She was also in the cast of the short-lived "Madman of the People" (1994–95). She appeared in recurring roles in several TV series, including L.A. Law, Falcon Crest, Picket Fences, Max Headroom, and Judging Amy. In 1987 she appeared in the film In Love and War.
In 1991 she guest appeared in Season 3 Episode 10 of the TV sitcom Wings titled "The Late Mrs. Biggins" where she played the former wife of Roy Biggins, and she also had the role of Mom in the cult film Don't Tell Mom the Babysitter's Dead. She starred in the 1992 Television miniseries The Burden of Proof. In 2005, Tomei guest appeared in an episode of The King of Queens. One year later, in 2006, she returned to Off-Broadway with an acclaimed performance in Sarah Ruhl's The Clean House. In 2007 she appeared opposite Kevin Kline and Jennifer Garner in the Broadway production of Cyrano: The Musical.
From 1997-2011, Tomei played guest roles on TV shows, such as 7th Heaven, Touched by an Angel, Second Time Around, The King of Queens, Weeds, Numb3rs, Kitchen Confidential, The Closer, Cold Case, Ghost Whisperer, Nip/Tuck, Rubicon, Necessary Roughness, and Star Trek: Voyager.
In 2017, she appeared in an episode of The Mick titled "The Grandparents", as Tippy Pemberton, the twisted, abusive grandmother of Sabrina, Chip and Ben.