Close to 30,000 men will die from prostate cancer in the United States in 2003. Hormonal ablation, the basis of systemic therapy, will invariably fail to control the progression of metastatic prostate cancer in the long run. For many years the only available therapeutic modalities for patients with metastatic androgen independent prostate cancer have been second-line hormonal maneuvers with estrogens or steroids and chemotherapy. So far, chemotherapy has been shown to confer adequate palliation but no overall survival benefit in prospective randomized controlled trials, and the only chemotherapy drugs approved by the US Food and Drug Administration are mitoxantrone and estramustine. Novel treatment strategies that aim at specific signaling pathways, apoptosis, differentiation, or specific membranous targets are being developed. Such new therapeutic modalities, along with recent data on immunotherapy and bone targeting strategies, will be reviewed here.