Born Stanley Osbourne, but always feeling she was a woman trapped inside a man's body, Bree (FELICITY HUFFMAN) who now dresses and tries to look, sound and act like a woman, believes she's ready for her final gender transformation -- surgery. Yet, her therapist, Margaret (ELIZABETH PENA), isn't so sure about the restaurant worker and part-time telemarketer's state of mind. And when she learns that Stanley/Bree has a son from a one-night stand in the past, she won't approve the surgery until Bree deals with the matter.
This has come up due to a phone call from New York where the police have 17-year-old Toby (KEVIN ZEGERS) in custody for shoplifting. The boy claims his mother is dead, that he doesn't get along with his abusive stepfather and that Stanley is his biological father. Accordingly, Bree travels to New York and bails him out, but not as his father/mother, but instead posing as a church missionary.
Toby wants to meet his father who he believes is a success, and thus Bree rents a car and the two drive from New York to Los Angeles, with her unsure when or if she'll inform him of her identity. Along the way, they have run-ins with an assortment of characters, including Calvin (GRAHAM GREENE) who takes a liking to Bree, seemingly unaware of his/her gender. When they reach Phoenix, they visit Bree's troubled sister Sidney (CARRIE PRESTON) and their parents -- Elizabeth (FIONNULA FLANAGAN) and Murray (BURT YOUNG) -- who still haven't accepted their son's gender changing decision.
With Toby figuring out part of Bree's secret before she admits to it, the unlikely duo continues on their road-based journey toward Los Angeles and an eventual resolution of their unique familial relationship.