Prostate specific antigen (PSA) is an invaluable tumor marker in the detection of early prostate cancer as well as a predictor of recurrence after treatment of localized disease. Current practice entails the use of factors such as pretherapy grade, stage and PSA, PSA doubling time, nature of previous therapy and patient age and functional status for a treatment recommendation. For a PSA relapse post radical prostatectomy, radiation therapy to the prostatic fossa is a primary therapeutic consideration. With careful patient selection, about 30 to 40% of patients are rendered disease free using this approach. For patients with radiation therapy as the primary treatment for their prostate cancer, salvage prostatectomy can be considered, but is rarely feasible. Systemic therapy with hormones is standard if patients are not candidates for the above mentioned salvage local therapies or if they relapse after exhaustive local therapies. Unfortunately androgen suppressive therapy is unlikely to induce cure, or prolonged remissions in PSA relapse prostate cancer. The strategy of addition of chemotherapy or biologic therapy to androgen suppressive therapy is under active investigation. The goal of this therapy is to make an impact on the time to progression to metastatic prostate cancer and correspondingly decrease prostate cancer related mortality. Preliminary results of studies incorporating early chemotherapy in combination with androgen suppressive therapy are encouraging, with improvement in time to progression and overall survival. The evaluation of biologic agents and agents with better toxicity profiles is ongoing. This is very important to make therapy widely applicable and to enable prolonged administration especially in a disease such as prostate cancer with a relatively long natural history. Strategies of adjuvant and neoadjuvant therapy in locally advanced prostate cancer are exploring the possibility of reducing the chance of PSA relapse by treating micrometastatic disease. This review discusses the current practices in risk stratification and management of PSA relapse prostate cancer. It also highlights the major clinical trials and areas of active investigation in this field.