Peter Highman (Robert Downey Jr.), a successful architect, is due to fly home from Atlanta to Los Angeles to be with his wife Sarah (Michelle Monaghan), who is about to give birth. On the way to the airport, he has a chance encounter with Ethan Tremblay (Zach Galifianakis), who is going to LA to be an actor and is planning to scatter his recently deceased father's ashes at the Grand Canyon. When Ethan misuses the words "terrorist" and "bomb" while talking to Peter, they are both escorted off the plane. This is only the first of a series of misadventures caused by the drastically dysfunctional Ethan. Peter, now on the No Fly List and missing his wallet, agrees to drive with Ethan to Los Angeles.