The mainstay of initial therapy of metastatic prostate cancer has not changed since 1941 when Huggins and Hodges described the efficacy of castration. The benefit of combining an androgen receptor blocker with medical castration has been debatable despite several large randomized trials and meta-analyses intended to answer the question. Recent phase III trial data with continuous versus intermittent androgen deprivation in newly diagnosed metastatic prostate cancer have established continuous therapy as the preferred approach at the present time. Novel and more potent inhibitors of androgen signaling have been developed in the past 5 years and have been validated in castration-resistant disease. Their role in management of hormone-sensitive metastatic prostate cancer is under evaluation in ongoing studies. As androgen deprivation therapy carries significant long-term toxicities including fatigue and loss of bone and muscle mass, an important element of clinical management is prevention and amelioration of these toxicities.