High-risk prostate cancer accounts for approximately 15% of all prostate cancer diagnoses. Patients with high-risk disease have an increased risk of developing biochemical recurrence, metastases, and death from prostate cancer. As the optimal management of high-risk disease in patients with prostate cancer continues to evolve, the contemporary treatment paradigm is moving toward a multidisciplinary integrated approach of systemic and local therapy for patients with high-risk disease. The strategies for definitive, adjuvant, and salvage local treatment, including radical prostatectomy or radiation therapy, serve as the backbone of therapy for patients with localized disease. Systemic therapy decisions regarding use in combination with surgery, choice of therapy (hormone therapy, chemotherapy), and treatment duration continue to be refined. As more effective hormonal agents populate the treatment landscape for advanced prostate cancer, including abiraterone and next-generation antiandrogens, an opportunity is provided to explore these treatments in patients with localized disease in the hope of improving the long-term outcome for patients. Integration of innovative blood and tissue-based biomarkers to guide therapy selection for patients with high-risk disease is an area of active research. Contemporary studies are using such biomarkers to stratify patients and select therapies. In this review, we summarize contemporary evidence for local treatment strategies, systemic therapy options, and biomarkers in development for the management of high-risk prostate cancer in patients.