Shlesinger is from Dallas, Texas, where she attended the private Greenhill School and participated on the school's Improv Team. She is Jewish. Shlesinger performed with ComedySportz Dallas. She attended the University of Kansas for her freshman year. She also participated in Semester at Sea. She then transferred to Emerson College in Boston and majored in Film. There she was a member of the campus' comedy sketch group, Jimmy’s Traveling All Stars, and refined her writing and editing skills. After graduating from college, she moved to Los Angeles to pursue stand-up. She was one of the most popular members of the "Whiteboy Comedy" group of stand-up comedians in Los Angeles which brought her to the stage at The Improv in Hollywood. Iliza is the ex-girlfriend of former NHL goaltender Jamie McLennan.
Shlesinger hosts The Weakly News on TheStream.tv. In 2007, Shlesinger won Myspace’s So You Think You're Funny contest and has been featured as the G4 network’s Myspace Girl of the Week. Her television credits include E! Network's Forbes Celebrity 100, TV Guide’s America’s Next Top Producer, John Oliver's New York Stand Up Show Season 3,Byron Allen’s Comics Unleashed, and History Channel’s History of a Joke. She has written for Heavy.com and had her own show on GOTV’s mobile network. Schlesinger is a contributor to "Surviving the Holidays with Lewis Black," a History Channel holiday special. Shlesinger was the narrator on the 2009 documentary Imagine It!² The Power of Imagination.
Shlesinger became the first female and also the youngest winner of NBC's Last Comic Standing in the series' sixth season. She was twice selected by other comedians to compete in the head-to-head eliminations and won both times. She appeared in The Last Comic Standing Tour.