Controversy remains regarding the preferred therapy for high-risk, clinically localized prostate cancer. High-risk prostate cancer represents a diverse disease entity for which accurate risk assessment is critical to informed counseling and clinical decision making. For men with high-risk features, electing surgery as a local definitive therapy should be based on the best available evidence rather than a surgeon's bias and experience. Patients classified with high-risk prostate cancer by common definitions do not have a uniformly poor prognosis after radical prostatectomy. Many cancers that are clinically categorized as high risk are actually pathologically confined to the prostate, and most of these men do not require additional long-term therapy after surgery. For some high-risk patients, an integrated approach combining local and systemic therapy may be advantageous. Available studies using adjuvant and neoadjuvant strategies have their individual strengths and weaknesses; unfortunately, none has provided persuasive evidence to dictate the standard of care in the high-risk setting. Therefore, results are eagerly anticipated from ongoing randomized trials exploring the merits of perioperative chemohormonal therapy in high-risk patients. This review discusses current limitations and challenges in accurately identifying high-risk patients and focuses on radical prostatectomy alone or as part of multimodal therapy for men with high-risk prostate cancer.