High-risk, localized prostate cancer represents a complex and diverse disease with many available treatment modalities. Patients are often deemed high risk because they are at increased risk for biochemical failure after primary intervention. However, these "high-risk" men may not be at significant risk of dying from their cancer. In this review, an attempt will be made to better define high-risk patients and help identify men at increased risk for mortality, not simply biochemical failure, after a diagnosis of localized prostate cancer. A review of available monotherapies as well as previously successful multimodality treatments will also be presented. Finally, this review will provide a glimpse into the future direction of high-risk prostate cancer multimodal therapy by providing a synopsis several current randomized clinical trials using effective systemic adjuvant therapies following local treatment.