For more than five decades, the preferred treatment for advanced prostate cancer has been suppression of androgen production by medical or surgical castration. However, all patients treated with androgen deprivation eventually develop resistant disease as manifested by increasing prostate-specific antigen levels, progressive disease on imaging studies, and ultimately worsening symptoms. The treatment of patients with hormone-refractory prostate cancer (HRPC), once thought to represent a relatively futile endeavor, has changed significantly in the past several years with the development of new therapeutics. One of the most important new treatment strategies involves secondary hormonal manipulation after the failure of primary androgen deprivation; this approach is predicated on the recognition that HRPC is a heterogenous disease. Some patients may respond to alternative hormonal interventions despite the presence of castrate levels of testosterone. Furthermore, the application of chemotherapeutic regimens has provided viable treatment options for patients with HRPC.