Since 2010, 5 new agents have been approved for advanced prostate cancer treatment. The American Urologic Association (AUA) published guidelines for the management of castration-resistant prostate cancer in 2013. These guidelines identify 6 index patients to consider when selecting the most appropriate treatment. No comparative trials have provided an approach to optimize the sequencing of these drugs. For the urologist, incorporating the guidelines into clinical practice typically requires a multidisciplinary team. This article provides an algorithmic approach based on indication and mechanism of action that complements the AUA guidelines to ensure patients receive the most optimal care.