When drag queen Anthony (Hugo Weaving) agrees to take his act on the road, he invites fellow cross-dresser Adam (Guy Pearce) and transsexual Bernadette (Terence Stamp) to come along.

In their colorful bus, named Priscilla, the three performers travel across the Australian desert performing for enthusiastic crowds and homophobic locals. But when the other two performers learn the truth about why Anthony took the job, it threatens their act and their friendship.