One of the current challenges in the evaluation of novel agents for the treatment of advanced prostate cancer is the identification of a surrogate end point for overall survival (OS). Prostate-specific antigen (PSA) levels have been used as a screening tool and a biomarker of response to both hormonal and cytotoxic agents. However, PSA levels do not seem to be a suitable surrogate end point for OS in trials of targeted agents for castrate-resistant prostate cancer (CRPC). These findings suggest the need for adopting measures of efficacy that more accurately reflect the mechanisms of action of these agents in phase II trials, in order to realize improvements in OS in the phase III setting. The Prostate Cancer Clinical Trials Working Group (PCWG2) have recently made recommendations for the design of future trials and advised that PSA levels should not be the sole criterion on which to base clinical decisions. Here, we appraise the end points that have been used in phase II and III trials in patients with CRPC, and highlight the need for the adoption of the PCWG2 guidelines, the recommendations of which include radiographic imaging, in addition to bone scintigraphy, and symptomatic or radiographic disease progression criteria.