Borstein was born in Highland Park, Illinois, a suburb north of the city of Chicago. Her parents, Julie and Ian Borstein, are both mental health professionals. She was raised in a Jewish family with roots in Germany, Hungary, Poland, Mongolia, and Russia. She attended San Francisco State University in San Francisco, California.

Borstein trained in improv at the ACME Comedy Theater, where she met her writing partner and future husband Jackson Douglas. Shortly after they began working together on the animated series Casper and Pinky and the Brain, Borstein left her position at an ad agency — where she had written print ads for Barbie — to become a full-time writer. In 1996, while still writing for Casper, Borstein worked on the show Zeo as the voice of Queen Machina, the queen of the Machine Empire.

In 1997, Borstein became a cast member on the third season of the sketch comedy show MADtv. She originally joined the cast as a featured player, but was upgraded to the repertory mid-season. Borstein was perhaps best known on MADtv for her character Ms. Swan; her other recurring characters included Eracist Anne, "Stick Chick" Echo, singer Jasmine Wayne-Wayne, child prodigy Karen Goddard, lounge singer Shaunda, News at Six's outside-the-studio reporter Sue Napersville, and Cordo the GAP troll. When Seth Green made recurring appearances on the show as mean boss Mr. Brightling, Borstein would play his mother, Mama Brightling.

While working on MADtv, Borstein met Seth MacFarlane, who was then preparing to launch the animated sitcom Family Guy on FOX. MacFarlane cast Borstein as the voice of key character Lois Griffin. After the show's debut in January 1999, Family Guy was cancelled by the network in 2000 and 2002 but returned in 2005; as well as her role as the voice performer for Lois and several other characters throughout the series (including a brief appearance as Ms. Swan in a 2005 episode), Borstein is also a producer and staff writer. She has made at least three guest appearances, once as Lois Griffin, on the Comedy Central animated program Drawn Together.

In 2000, Borstein was cast as Sookie St. James in the WB drama Gilmore Girls. She portrayed Sookie in the pilot, but her MADtv contract prevented her from continuing in the role, which was recast with Melissa McCarthy. Borstein made recurring appearances on Gilmore Girls throughout the show's run, first as the harpist Drella and later as Miss Celine, a celebrity fashion advisor.

Borstein's film roles include the school principal in The Lizzie McGuire Movie, the best friend of Halle Berry's character in Catwoman, and an employee at CBS News in Good Night, and Good Luck. She also had an uncredited cameo in the Will Ferrell movie Kicking & Screaming as an obnoxious coffee shop patron. She also had a small role in the movie Bad Santa.

Borstein was cast as a press secretary in the 2007 sitcom pilot The Thick of It, but the series was not picked up for broadcast. She can be seen in the upcoming comedy For Christ's Sake, which is directed by her real-life husband Jackson Douglas. The film is currently in post-production.

Borstein's production company is called Crackerpants, Inc.

MADtv impressions

Borstein's celebrity impression on MADtv included:

• Anne Robinson
• Betty Ford
• Beverly Mitchell
• Björk
• Chelsea Clinton
• Cindy Williams
• Deborah Rowe
• Dolly Parton
• Ellen DeGeneres
• Queen Elizabeth II
• Fran Drescher
• Frances Bavier
• Geri Halliwell
• Hallie Kate Eisenberg

• Jamie-Lynn Sigler
• Jane Pauley
• Janeane Garofalo
• Janet Reno
• Jean Stapleton
• José Carreras
• Joyce DeWitt
• Julie Cypher
• Kristin Davis
• Linda Ellerbee
• Marie Osmond
• Mary Bono
• Maura Tierney

• Megan Mullally
• Melanie Griffith
• Monica Lewinsky
• Natalie Merchant
• Natalie Schafer
• Patsy Ramsey
• Regis Philbin
• Ron Howard
• Rose Marie
• Roseanne Barr
• Rosie O'Donnell
• Tori Spelling
• Vivian Vance

Borstein is married to actor and writer Jackson Douglas, whom she met while studying improv at the ACME Comedy Theater. Douglas proposed to her during the taping of a MADtv skit; the couple married in 1999. In the "Stewie Kills Lois" DVD commentary — at the time, she was pregnant — she jokes about the possibility of naming her baby Stewie.The couple's son, Barnaby Borstein Douglas, was born on September 8, 2008.

Borstein plays the harp, as she demonstrated on Gilmore Girls.