Bree er en pæn, meget troende kristen dame, som lever et yderst regelret liv, hvis man altså lige ser bort fra, at hun i virkeligheden er en transseksuel mand. Bree har hele 2 jobs, hvor hver en øre bliver sparet sammen til den store kønsskifteoperation. En dag modtager hun et mærkeligt opkald. Det lader til at hun har en søn, som er et resultat af en kikset affære fra dengang, hun levede som mand. Drengen hedder Toby, er i ungdomsfængsel og har hårdt brug for sin fars hjælp.
Jerri Blank is a former prostitute and junkie whore who returns to high school as a 46-year-old freshman at Flatpoint High. Jerri ran away from home and became 'a boozer, a user, and a loser' after dropping out as a teenager, supporting her drug habits through prostitution, stripping, and larceny. She has been to prison several times, the last time because she 'stole the TV'. At home, Jerri's father Guy is comatose, although he seems perfectly capable of amazing feats. Her stepmother Sara is vain and bitter, and stepbrother Derrick is a bullying jock. Jerri tries to do things the right way but always ends up learning the wrong lesson. Her hijinks often involve, either directly or indirectly, neurotic history teacher Chuck Noblet and his secret lover, sensitive art teacher Geoffrey Jellineck.
