Alfie (Anthony Hopkins) and Helena (Gemma Jones) divorce. Helena begins seeing fortune teller Cristal (Pauline Collins) for spiritual advice. Their daughter Sally (Naomi Watts) has a troubled marriage with author Roy (Josh Brolin), who once wrote a successful book, and is now anxiously waiting for response from his publisher about the manuscript of his newest one. Helena helps pay their rent.
Alfie marries a prostitute, Charmaine (Lucy Punch). Roy falls for Dia (Freida Pinto), a musicologist he sees through a window near his and Sally’s flat, who is engaged to another man. Sally considers having an affair with Greg (Antonio Banderas), her new boss at an art gallery who she confesses she has feelings for but Greg confesses he is having trouble at home and eventually it turns out he is having an affair with Iris (Anna Friel), Sally's protégé. Helena begins a friendship with Jonathan (Roger Ashton-Griffiths), the keeper of an occult bookshop, which develops into romance.
Roy's book is rejected. He hears that a friend, who is also a writer, has died in an accident, and of whom only Roy knows that he had just finished a manuscript that he had not shown to anyone else yet. Roy steals it, and claims it is his work. It is well received. He convinces Dia to break off her engagement, and moves in with her.
Alfie gets into a fight and worries about Charmaine's high expenses. He asks Helena to make a new start with him, but she refuses. Charmaine has sex with another man and gets pregnant. Alfie wants a DNA test to find out whether he is the father, while Charmaine argues that it does not matter.
Sally quits her job and asks Helena for a loan she promised, for setting up her own art gallery, but Helena refuses because according to Cristal it is astrologically a bad time. Sally is furious. Roy is informed that there was a mix-up of the people killed in the accident and is shocked to hear that the friend whose manuscript he stole is actually in coma and recovering.
In the end, all are dissatisfied with their choices, except for Helena. She has acquired from Cristal a belief in reincarnation, and sees her life now as only one episode in her series of lives. Jonathan shares her esoteric beliefs, and they receive the blessing of his deceased wife for the new relationship via seance.