Lisa Edelstein was born to Jewish parents Alvin and Bonnie Edelstein in Boston, Massachusetts, USA. Her father is a pediatrician in New Jersey at Chilton Memorial Hospital. One of three children, she was raised in Wayne, New Jersey and attended Wayne Valley High School, graduating in 1984. She moved to New York City at the age of 18 to study theatre at New York University's Tisch School of the Fine Arts. While living in New York, she became involved in the club scene known only as "Lisa E.", and caused enough of a stir in the community to be dubbed New York City's "Queen of Downtown" by writer and fellow celebutante James St. James, who briefly refers to Edelstein in his 1999 book Disco Bloodbath.

After being dubbed a "celebutante" by Newsweek magazine during her club kid days, Edelstein used her newfound celebrity to write, compose and star in an original musical called Positive Me in response to the growing AIDS crisis of the 1980s. After a brief stint hosting Awake on the Wild Side for MTV in 1990, she spent the early '90s appearing in guest roles on several popular comedies, including Mad About You, Wings, The Larry Sanders Show and Seinfeld, where she played George Costanza's frustrated girlfriend.

Bigger roles in TV dramas soon followed, among them the lesbian sister on ABC's Relativity in 1996; Rob Lowe's date turned high-priced call girl on The West Wing in 1999; a male-to-female transsexual on Ally McBeal in 2000 and Ben's girlfriend on Felicity in 2001. She also continued to land guest star spots on shows such as ER, Frasier, Just Shoot Me, Without a Trace and Judging Amy.

The actress has lent her voice to several animated programs including King of the Hill, American Dad, Superman: The Animated Series (as Mercy Graves, Lex Luthor's bodyguard, a role she later reprised in several episodes of Justice League) and the 1997 video game adaptation of Blade Runner. Edelstein's film credits include What Women Want with Mel Gibson Keeping the Faith with Ben Stiller, As Good as it Gets with Jack Nicholson and Daddy Day Care with Eddie Murphy

In 2004, she was cast as Dr. Cuddy, the Dean of Medicine at Princeton-Plainsboro Teaching Hospital and frequent character foil to title character Gregory House (Hugh Laurie on FOX's hit show House, M.D.. She will star in Lifetime Movie Network's Special Delivery alongside Brenda Song

Edelstein currently resides in a century-old home in Los Angeles with her cat and three rescue dogs. She is a vegetarian and an avid practitioner of Mysore style Ashtanga Yoga. She frequently volunteers for the Best Friends Animal Society. In her spare time she enjoys writing, painting and composing music.