The management of high-risk, localized prostate cancer remains a formidable challenge despite significant technical advances in surgery and radiation therapy. Treatment outcomes of radiation therapy are improved by the addition of adjuvant androgen deprivation therapy, whereas, with surgery, oncologic results are enhanced with either postoperative radiation therapy or androgen deprivation therapy in select cases. In high-risk prostate cancer, disease recurrence after primary therapy may occur at either distant or local sites. Ongoing studies are in the process of evaluating systemic therapy for the eradication of local and micrometastatic disease. Neoadjuvant therapies offer the opportunity to maximize local control as a path to improved outcomes and critically evaluate agent effectiveness in the target tissue. The treatment for high-risk localized prostate cancer is in evolution. It is likely that the development of effective strategies based on understanding prostate tumor biology will lead to significant advances in the treatment of this disease.