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Six different treatments have demonstrated improved survival in phase III trials targeted to patients with metastatic castration-resistant prostate cancer (mCRPC). Front-line therapeutic options for mCRPC include docetaxel, sipuleucel-T, abiraterone and radium-223. Post-docetaxel options include cabazitaxel, abiraterone, enzalutamide and radium-223. Despite much progress in recent years, much is yet unknown and debates occur over optimal treatment choices and sequences. None of the new agents have been compared to one another, thus physicians in practice today must make choices based on non-randomized comparisons, toxicity considerations and various assumptions. Abiraterone is now moving into the front line mCRPC space given recent regulatory approvals and enzalutamide will follow soon. Both of the hormonal agents have less toxicity when compared to chemotherapeutic options and both of these hormonal agents are expected to be used in a considerable number of mCRPC patients in the years ahead. Little data are available for the post-abiraterone or post-enzalutamide setting. In this review the currently available sequencing data are summarized and interpreted. It is now clear that cross resistance is a potential issue between various treatments, especially those agents that target the androgen axis. This review highlights the need for additional studies to optimize the current treatments for these patients.