After local treatment, a substantial proportion of patients with prostate cancer present with rising prostate specific antigen (PSA) serum levels as the only indication of disease activity. Evolving data derived from large databases that were predominantly retrospectively evaluated show that the natural history of these patients is quite variable. Various clinical and pathologic parameters have been shown to predict for the probability of development of distant metastasis, including the surgical Gleason score, time of PSA relapse after primary treatment, and PSA doubling time (PSADT). The PSADT appears to be the most important predictor of development of distant metastasis and prostate cancer-specific mortality. At present, no data support a standard management approach for these patients, and clinical trials pose a major challenge in view of the methodologic complexities involved. Patients and treating physicians should make major efforts to participate in clinical trials in this patient population.