I think like 85% and then the other 15 is the experience of a woman. We usually cull a lot of stories from what happened to us and our friends, so I’d say a lot of it is. I always feel like rejection is my petrol. That’s what keeps me going.
Kightlinger was a featured player for the Saturday Night Live (season 20) (1994-5).
In 1997, Kightlinger appeared in Who's the Caboose?, an independent movie comedy starring Sarah Silverman and Sam Seder.
Kightlinger's book Quick Shots of False Hope was published in 1999. The New York Times Book Review described it as "funny and disturbing", "memorable", and an "idiosyncratic and darkly comic debut." As of 2006, she was adapting the book for film.
In 2003, she directed her first documentary, Sixty Spins Around the Sun, which chronicles the New York City street movement to repeal the Rockefeller Drug Laws. It focuses on political satirist turned Activist Randy Credico and his fight to repeal the laws. The film follows Credico to Tulia, Texas during a racially motivated drug bust, which is the subject of an upcoming film starring Halle Berry. Included in this documentary are stand-up comics Larry David, Colin Quinn, Don Gavin, Vanessa Hollingshead and Nick DiPaolo. It won Best Documentary at the 2003 Empire State Film Festival, 2003 Boston International Film Festival, and 2005 Beverly Hills Film Festival (Jury Award). Her film credits include: DaddyDaycare, Kicking & Screaming, Anchorman: Wake up Ron Burgundy, The Truth About Lies and The Outdoorsman.
In 2005 she starred in the short film Dysenchanted, directed by Terri Edda Miller, which received critical acclaim.
In 2006, Kightlinger appeared in The Minor Accomplishments of Jackie Woodman, a comedy series. Asked how much of the series was based on her personal experience, she said:
Kightlinger has written several shorts for Funny or Die and Atom.com, including “American Heroine,” in which she starred, and “Roy Fabcock: Legendary Lover.” (2010).
In 2017, she had a cameo in The Lego Batman Movie, voicing the role of Grace Balin/Orca, as well as Reporter Pippa.