Approximately one-third of patients who undergo radical prostatectomy for prostate cancer will develop a detectable prostate-specific antigen (PSA) level within 10 years. Biochemical recurrence of disease is defined as a rising PSA level in the absence of clinical or radiographic evidence of disease. Management of PSA recurrence is controversial, as prostate cancer may take an indolent course, or it may aggressively develop into metastatic disease. The only potentially curative treatment for biochemical failure after prostatectomy is salvage radiotherapy. Noncurative treatment options include hormone therapy or clinical trials of a novel systemic agent. This article will address management options for a rising PSA level after prostatectomy, as well as ongoing studies exploring molecular biomarkers as prognostic tumor markers and potential targets for prostate cancer therapy.