Therapeutic options for patients with metastatic prostate cancer relapsing from primary hormonal therapy are limited. On the selective discontinuation of flutamide in patients that have relapsed on combined androgen ablation, a third of the patients will show a significant clinical benefit for 4-6 months. A multivariate model has identified prolonged exposure to combined androgen blockade, high baseline alkaline phosphatase and prolonged flutamide exposure as prognostic factors for patients that have a significant prostate-specific antigen (PSA) decline after the withdrawal of flutamide. This phenomenon has also been described with bicalutamide and other antiandrogens, and thus has been more appropriately renamed the endocrine withdrawal syndrome. The molecular basis for this endocrine withdrawal syndrome is not completely understood but data suggest that mutations in the androgen receptor may be responsible for the paradoxical effect observed. Recognition of this syndrome has introduced a non-toxic therapy for advanced prostate cancer patients and has had a dramatic impact on the interpretation and design of clinical trials in patients with 'hormone refractory disease'.