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In the last three years, five novel treatments have been shown to improve survival in metastatic castration-resistant prostate cancer (CRPC). These novel treatments have distinct mechanisms of action: tubulin-binding chemotherapy (cabazitaxel); immunotherapy (sipuleucel-T); CYP-17 inhibition (abiraterone); androgen receptor (AR) blockade (enzalutamide); and radioisotope therapy (radium-223). For a number of years, docetaxel was the only treatment with a proven survival benefit for patients with CRPC. Therefore, somewhat artificially, three treatment spaces for drug development in CRPC have emerged: pre-docetaxel; docetaxel combinations; and post-docetaxel. For patients progressing after docetaxel-based chemotherapy, treatment options available outside of clinical trials now include abiraterone, cabazitaxel and enzalutamide. Prospective data on how to best use these novel agents sequentially are not available. Clinicians face the difficult task of choosing between treatment options for individual patients to maximize patient benefit. Treatment evaluation in patients with CRPC remains challenging due to the predominance of bone metastatic disease and the lack of validated surrogate markers for survival. This review summarizes the data available with regards to sequencing of the novel treatments for CRPC.