The optimal treatment of the patient at high risk for local recurrence of prostate cancer after radical prostatectomy is controversial. Similarly, there is much controversy over how to treat patients with a rising prostate-specific antigen (PSA), but without overt metastases, after radical prostatectomy. A recent randomized controlled trial of adjuvant radiotherapy versus observation following radical prostatectomy shows a significantly higher freedom from recurrence for patients receiving adjuvant radiotherapy, which may help to resolve the question of whether or not to wait for a rise in the PSA before offering treatment. For patients with biochemical recurrence after prostatectomy, part of the problem lies in the difficulty in determining whether a rise in the PSA is a sign of local recurrence or a harbinger of distant metastases. Making this distinction is critical, since patients with local disease may be cured with radiation therapy to the prostate bed, whereas those with metastatic disease will require a different treatment approach. In this article, we discuss the factors that must be taken into consideration when making treatment recommendations for these patients. In addition, approaches to the evaluation and management of patients with this difficult clinical problem are presented.