Theatre director Caden Cotard (Philip Seymour Hoffman) is mounting a new play. His life (catering to suburban blue-hairs at the local regional theatre in Schenectady, New York) is looking bleak. His wife Adele (Catherine Keener) has left him to pursue her painting in Berlin, taking their young daughter with her. His therapist, Madeleine Gravis (Hope Davis), is better at plugging her best-seller than she is at counselling him.

A new relationship with the alluringly candid Hazel (Samantha Morton) has prematurely run aground. And a mysterious condition is systematically shutting down each of his autonomic functions, one by one. Worried about the transience of his life, he leaves his home behind. He gathers an ensemble cast into a warehouse in New York City, hoping to create a work of brutal honesty.

The years rapidly fold into each other, and Caden buries himself deeper into his masterpiece, but the textured tangle of real and theatrical relationships blurs the line between the world of the play and that of Caden's own deteriorating reality.