Biochemical failure after curative-intent therapies is an increasingly common dilemma confronting patients and physicians. No definition of biochemical failure exists that can be applied to all forms of treatment and that is not to some degree affected by the follow-up interval, pretreatment prognostic factors, or the frequency of prostatic-specific antigen (PSA) testing. Available imaging techniques lack sensitivity in detection of occult micrometastases. Prognostic factors such as tumor characteristics and PSA kinetics should be considered when recommending second-line therapies. For those patients with suspected localized recurrence, second-line treatment with salvage therapies may provide long-term disease control. Hormonal therapy, although most commonly employed for PSA recurrence, is of palliative benefit only. Currently, the most appropriate therapeutic intervention for asymptomatic patients with evidence of biochemical failure remains undefined.