He is most famous for his gig as host of Late Night with Conan O'Brien. O'Brien is scheduled to take the reigns from Jay Leno as host of The Tonight Show in 2009.

O'Brien moved to Los Angeles after graduating from Harvard to join the writing staff of HBO's Not Necessarily the News. He spent two years with the show, and performed with improvisational groups like The Groundlings.

In 1988, Saturday Night Live's (SNL) executive producer Lorne Michaels hired O'Brien as a writer. In 1989, he and the other SNL writers were awarded an Emmy Award for Outstanding Writing in a Comedy or Variety Series.

After leaving SNL, O'Brien signed on as a writer and producer for the Fox series The Simpsons, where he also became a supervising producer.