Prostate cancer is a leading cause of morbidity and mortality among males. Androgen ablation as initial therapy for advanced prostate cancer provides high response rates but does not cure disease, as nearly all men with metastases will eventually progress to hormone-refractory prostate cancer (HRPC). Present chemotherapy regimens for HRPC can provide palliation and have recently demonstrated an increase in overall survival. Over the past 2 decades, these regimens represent clear advances in the treatment of metastatic prostate cancer but also demonstrate that newer therapies are needed. Studies are ongoing to provide viable alternatives among traditional cytotoxic therapies as well as among novel agents targeting specific molecular pathways. This article reviews some of the newer therapies being developed and evaluated, including the epothilone analogues, human epidermal growth factor receptor pathway inhibitors, angiogenesis inhibitors, and endothelin receptor antagonists.