An Illinois native, Borstein moved to Los Angeles with her family in 1980, going on to attend San Francsico State University and join the Los Angeles-based comedy troupe ACME Comedy Theater. While performing with the group at the Big Stinkin' International Improv and Sketch Festival in Austin, Texas, she was discovered by a "Mad TV" casting agent. Borstein began her work on the show in 1997 and soon became an audience favorite with memorable characterizations like that of obnoxious and indecipherable nail salon worker Ms. Swan. She proved a versatile and valuable member of the "Mad TV" team as a writer in addition to doing solid celebrity impersonations that ranged from Chelsea Clinton to Regis Philbin. She would remain with the series through the 2001-2002 season.
Following a brief cameo in the feature "Coyote Ugly" (2000) Borstein had a recurruing role on The WB's family drama "Gilmore Girls" (2000- ), playing Drella, a prickly harp player whose biting comments are in contrast to her beautiful music, throughout the first season, and she returned to the show in 2003 as a new character, Miss Celine. Borstein would also appear on episodes of such series as "Friends," "Frasier," and "3-South."
Borstein's unique talent with voices made for a successful career in animation. A writer for such animated series as "Casper" (Fox) and "Pinky and the Brain" (The WB) earlier in her career, she took on voice work, portraying the character of Lois Griffin on Fox's "Family Guy" beginning in 1999. Here she brought life to the surprisingly calm, long-suffering wife of the boorish title character and mother of two trying teens and a maticidal infant. Beginning in the second season, Borstein would additionally contribute to the series as a staff writer.
The comdienne also lauched a successful side career as a character actress in a variety of high profile films, including "Bad Boy" (2002), "Showtime" (2002), "The Lizzie Maguire Movie" (2003) and "Bad Santa" (2003). She had her most visible role as Halle Berry's man-crazy gal pal Sally in 2004's "Catwoman," providing a much-needed comic spark to her scenes in the otherwise dismal adventure.