Ten years ago, the clinician treating metastatic castration-resistant prostate cancer (CRPC) had palliative options for treatment of symptomatic patients, such as the combination of mitoxantrone combined with prednisone, as well as isotope therapy. In 2004, docetaxel-based chemotherapy regimens were shown to provide an overall survival benefit for patients with CRPC. Today, the prostate cancer oncologist is in the enviable position of having six U.S. Food and Drug Administration-approved agents to choose from: immunotherapy (sipuleucel-T), hormonal therapies (abiraterone, enzalutamide), radiopharmaceuticals (radium-223), and chemotherapy (docetaxel, cabazitaxel), in addition to agents being administered in clinical trials. In general, the sequencing of these drugs is based upon the entry criteria from the phase III trials that led to their approval. Selection of treatment is based on symptoms, sites of disease (bone vs visceral) and types of prior treatment (docetaxel-ineligible vs. pre-docetaxel vs post-docetaxel setting). Unfortunately, there is a lack of useful correlative biomarkers in prostate cancer to help oncologists select treatment. This problem is best illustrated in the post-docetaxel castration-resistant setting, for which there are indications to use all five other approved agents. In this review we will outline an approach to sequencing these new therapies, with particular attention paid to the biology of CRPC.