Patients who present with advanced prostate cancer and who are treated with primary endocrine therapy have a significantly longer time to progression and a clear survival advantage if their serum PSA concentration normalizes. The prognostic significance of normalization of PSA is independent of other prognostic measures. Normalization of serum PSA at month 3 is the earliest and most highly correlated predictor of response. Most patients (80%-85%) who have disease progression while on hormonal therapy will show a rising PSA 6 to 12 months before other clinical findings become abnormal. A rising PSA in the hormonally treated patient, even if the values are within the "normal" range, signals impending clinical progression. These patients should be considered for second-line hormonal therapies or alternative salvage protocols, as a theoretically favorable window of opportunity may exist when the PSA begins to rise. Patients treated with second-line therapies should also undergo serial PSA measurements; those responding with an 80% to 90% decrease in serum PSA are statistically more likely to enjoy a prolonged response.