Harris, born in Worthington, Ohio, graduated from Worthington High School in 1986. She went on to graduate from Otterbein College, in 1989, majoring in theatre.

Harris performed with the Los Angeles, California, improvisational comedy troupe the Groundlings, and taught for a time with the Groundlings school.

She debuted on television in a 1993 episode of SeaQuest DSV.

After an appearance on Star Trek: Voyager in 1997, Harris went on to a recurring role in The WB's Sister, Sister.

Other television credits include a stint as a correspondent for The Daily Show's 2002–2003 season, as well as roles on The Sarah Silverman Program, Reno 911!, The West Wing, The Good Guys, Friends, Curb Your Enthusiasm, Monk, CSI: Crime Scene Investigation and, in November 2008, Desperate Housewives.

Harris played the supporting role of Kevyn Shecket, Kirstie Alley's personal makeup artist, on the Showtime series Fat Actress in 2005. She played Cooper in the ABC sitcom Notes from the Underbelly.

Her film credits include roles in Best in Show, A Mighty Wind, For Your Consideration, Kicking & Screaming, and Daddy Day Care.

In the 2009 comedy The Hangover she plays Melissa, girlfriend to Ed Helms's character Stu. She previously co-starred with Helms on The Daily Show.

She played Greg's mother in the film Diary of a Wimpy Kid (2010), and reprised the role in the two sequels.

Harris hosted Smoking Gun TV in 2004, and has made multiple appearances on such VH1 documentaries as I Love the '80s, I Love the '90s, and Best Week Ever.

Off-Broadway Harris has performed in Love, Loss, and What I Wore.

Harris' TV commercial work includes ads for Dinty Moore, Avis, Expedia, Quaker Oats, T-Mobile, Geico, and a Super Bowl commercial for the 2010 Census.

She is the voice of turtle Karolyn Slowsky in the Comcast Slowskys television commercials.

Harris signed on to ABC's Cougar Town, TVGuide.com confirmed. She plays Shanna, a woman that the network describes as being the "nemesis" of Jules.

Also on ABC, she made a guest appearance in the Modern Family episode "Caught in the Act" as a restaurateur.

Harris stars in the indie comedy/drama film Natural Selection which was well received at its 2011 South by Southwest debut, winning both jury and audience awards for best narrative feature, in addition to best screenplay, best editing, and best score/music. Harris received the breakthrough performance award for her role in Natural Selection.

In 2015, Harris was cast as Linda, Lucifer's therapist in the FOX television series Lucifer. The show was initially met with mixed reviews, but has maintained a supportive fan base throughout the series. When Fox cancelled the show in May of 2019, it was quickly picked up by Netflix for a fifth and final season.

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