Shlesinger hosted The Weakly News on TheStream.tv from July 7, 2007 to April 9, 2012. She also hosted Excused, a syndicated American reality-based dating competition series, which ran from 2011 to 2013. She co-stars in the 2013 film Paradise. She began a podcast called Truth and Iliza in August 2014. Featuring Celebrity guests & personal friends, the semi-weekly podcast is a forum for discussing things which bother her and those on the show, with punk theme song performed by Being Mean to Pixley.
In 2008, Shlesinger became the first woman, and 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 each time. She appeared in The Last Comic Standing Tour.
Shlesinger contributed to Surviving the Holidays, a History Channel holiday special, with Lewis Black, and narrated the 2009 documentary Imagine It!² The Power of Imagination. In 2010, she released an on-demand comedy video, Man Up and Act Like a Lady, and an on-demand comedy album, iliza LIVE, on her website, via The ConneXtion. Around the time of these releases, Shlesinger appeared in a Business comedy video series for Slate.
Shlesinger's first comedy album and video, War Paint, was recorded on December 1, 2012 at The Lakewood Theater in Dallas, Texas, and released on Netflix on September 1, 2013. Her second stand-up special, Freezing Hot, was recorded in Denver, Colorado and premiered on Netflix in January 23, 2015. Her third Netflix stand-up special, titled Confirmed Kills, was recorded at The Vic Theatre in Chicago, Illinois, and premiered on Netflix on September 23, 2016.
On July 13, 2016, the ABCdigital original short-form digital comedy series Forever 31, created by and starring Shlesinger was released.
In mid 2017, Shlesinger became engaged to her boyfriend, whose identity she has protected by using the pseudonym "Smoky Husky." She has since posted updates on her Facebook page, including pictures and videos from her bachelorette party in early 2018, and photos of her engagement ring.
