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The medical management of men with castration-resistant prostate cancer (CRPC) has changed dramatically in the last decade. Men can now access several agents developed to extend survival, delay morbidity caused by complications, and preserve quality of life. Strategies to extend survival include docetaxel and cabazitaxel, the CYP-inhibitor abiraterone acetate, the second-generation androgen receptor antagonist enzalutamide, sipuleucel-T immunotherapy, and the α-emitting radionuclide (223)radium. These novel therapies have fostered interest in translational science and a deeper understanding of the underlying biology of CRPC. This article summarizes clinical data and unresolved issues in the use of current and emerging CRPC therapies.