A Detroit native whose entry into the comedy scene wasn't entirely intentional, the former performance artist decided to try her hand at humor when a non-comedic performance at the San Francisco Art Institute elicited unexpected laughs from the audience. Subsequently realizing the absurdity inherent in overly serious performance art, Rajskub soon adjusted her act to become a parody of performance art. The unique take on live comedy quickly caught on with audiences, and shortly thereafter, Rajskub was approached by Bob Odenkirk and David Cross and asked to join the cast of their upcoming HBO stream-of-consciousness comedy series Mr. Show. A somewhat bitter falling out with series co-creator Cross found Rajskub departing from the series after a year to take a job at Seattle's Best Coffee, but her career as a caffeine dealer would quickly come to an end when Garry Shandling caught wind of her act.

Subsequently cast as the enthusiastic but somewhat awkward talent booker on The Larry Sanders Show, Rajskub also began to branch out into feature territory with supporting roles in such films as Bury Me in Kern County and the mockumentary The Thin Pink Line (both 1998). Blink-and-you'll-miss-her roles in such high-profile releases as Man on the Moon and Road Trip were quick to follow, with a small but memorable turn as a bubble-wrapped cult member in Dude, Where's My Car? preceding yet another fleeting appearance in the "Fiction" segment of director Todd Solondz's Storytelling.

By this point, Rajskub had expanded her presence on television with a recurring role in Veronica's Closet, and after appearing with Girls Guitar Club bandmate Karen Kilgariff in the independent drama The Anniversary Party, she made a move back to the small screen with the ill-fated sketch comedy series The Downer Channel. If that series didn't last long, Rajskub didn't need to worry since appearances in such features as Punch-Drunk Love, Sweet Home Alabama, and Legally Blonde 2 found her slowly drifting toward more substantial roles on the silver screen. After becoming a frequent player in the 2003-2004 season of the wildly popular television series 24, Rajskub took an ominous turn with her role as Lynette "Squeaky" Fromme in the 2004 made-for-television remake Helter Skelter.