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Klein has served as a consulting producer for the Netflix series animated sitcom Big Mouth since 2017, and provides the voice for one of the series' main female characters, Jessi Glaser.

Klein released her debut book in July 2016, You'll Grow Out of It, which became a New York Times best seller.

She has been an executive producer and writer for Inside Amy Schumer on Comedy Central since its debut, and won a Primetime Emmy Award for Outstanding Variety Sketch Series in 2015 for her work on the show. She was also a consulting producer on the series "Transparent" in 2016.

Klein's Comedy Central Presents special aired on March 4, 2011.

Klein made her first-time appearance as a panelist on NPR's comedy-news quiz show Wait Wait... Don't Tell Me! on June 25, 2011. She was the first female guest host of the program on March 11, 2017.

In 2009, she wrote and co-starred in Michael and Michael Have Issues on Comedy Central. She also worked as a writer on Saturday Night Live during the 2009-2010 season.

In 2004 Klein appears twice in the Season 2 "Wayne Brady Show" episode of Chappelle's Show: first, in the boardroom to inform Dave of how replaceable he is on the show, and later she along with Neal Brennan are gassed by Chappelle "in the wings" just before Chappelle confronts Wayne Brady to take his show back.

Jessi Ruth Klein (born August 18, 1975) is an American writer, actress and stand-up comedian from New York City. Klein has regularly appeared on shows such as The Showbiz Show with David Spade and VH1's Best Week Ever and has performed stand-up on Comedy Central's Premium Blend. She provided commentary for CNN in the debates of the 2004 presidential election. A self-proclaimed "geek", Klein has appeared on the television specials for My Coolest Years: Geeks on VH1 and Rise of the Geeks on E!. Klein also provided the voice of Lucy in the animated pilot for Adult Swim's Lucy, the Daughter of the Devil.