He portrayed "Francis the Driver" in the Judd Apatow hit comedy Superbad and had supporting roles in films such as Pineapple Express, Paul, Role Models, Wanderlust, and I Love You, Man. In July 2008, Lo Truglio starred with Bill Hader and Jason Sudeikis in the web series The Line on Crackle. He has appeared on the comedy podcasts Comedy Bang Bang, Never Not Funny, and Superego.

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