His second feature film The Ten, starring Winona Ryder and Paul Rudd (and a large ensemble cast of well-known actors), had a short theatrical run and was released on DVD on January 15, 2008.

Wain's third feature, Role Models, starring Paul Rudd, Seann William Scott, Christopher Mintz-Plasse, Jane Lynch and Elizabeth Banks, was his first widely released film.

Released in theaters on November 7, 2008, the film received positive reviews from critics and fans alike, as well as earning $19 million on its opening weekend.

[4] Wain starred in a web series titled Wainy Days on the website My Damn Channel, which ran for five seasons and ended in January 2012.

The series follows a fictionalized version of Wain through his everyday life as he tries to romance numerous women and discusses his problems with his friends at the sweatshop where he works.

Elizabeth Banks, Jonah Hill, Jason Sudeikis, Rob Corddry, Thomas Lennon, Josh Charles, Paul Rudd, and Michael Ian Black, and various other Stella, The State and Wet Hot American Summer alumni have all guest-starred in various episodes.

[5] In 2018 Wain directed A Futile and Stupid Gesture, a feature film biography of National Lampoon founder Doug Kenney, starring Will Forte, Domhnall Gleeson and Joel McHale.

In the COVID-19 pandemic, Wain founded the Middle Aged Dad Jam Band, in which he plays drums alongside fellow State alumnus Ken Marino.