Ketoconazole is a nonselective steroid 17α-hydroxylase/17,20 lyase (CYP17A1) inhibitor that has been used, off-label, as a second-line therapy for castration-resistant prostate cancer (CRPC). The drug has shown clinical efficacy without survival benefit. Despite not improving survival, ketoconazole has beneficial characteristics, such as its low cost, a relatively favourable toxicity profile compared with chemotherapy, and its efficacy both before and after chemotherapy. The approval of several new, highly effective treatments, including abiraterone acetate, enzalutamide, and apalutamide, warrants re-evaluation of the role of ketoconazole and other classic agents in achieving the optimal timing and sequencing of available agents to prolong survival and maintain patients' quality of life. In the current CRPC treatment landscape, we believe that ketoconazole can be considered in patients with nonmetastatic CRPC and in those with metastatic CRPC who do not respond to, tolerate, or have access to chemotherapy and other standard therapeutic options.