The treatment landscape for advanced prostate cancer is evolving rapidly, with new agents and strategies, and more optimal use of existing therapies under constant development. Efforts were focused on better understanding of the biology of the disease. This effort has paved the way for a more contemporary and effective therapies to be developed. There are now 6 FDA-approved therapies that increase overall survival. These include the immunotherapy sipuleucel-T; the 2 androgen pathway inhibitors: abiraterone acetate and enzalutamide; 2 chemotherapy drugs: docetaxel and cabazitaxel; and the radionuclide: radium-223. Advanced prostate cancer may be one of the few cancers for which multiple chemotherapy and nonchemotherapy regimens are considered as standard. Several recently published clinical trials have demonstrated the suprising activity of chemotherapy-free strategies, and we should not be too eager to discount these "old-fashioned" treatments. Optimal sequencing is still unclear because new therapies have proliferated so quickly that comparative data are limited. In this short communication, we identify current challenges and unmet needs in advanced prostate cancer and provide an overview of their respective clinical activity, while highlighting distinctions between therapies.