Prostate cancer is the most common cancer diagnosed in American males, and is the second leading cause of cancer-related deaths. Most patients who develop metastatic disease will initially respond to androgen deprivation, but response is invariably temporary. Most patients will develop androgen-independent ("hormone-refractory") disease that results in progressive clinical deterioration and ultimately death. This progression to androgen independence is accompanied by increasingly evident DNA instability and alterations in genes and gene expression, including mutations in p53, over-expression of Bcl2, and mutations in the androgen receptor gene, among others. Treatment options for hormone refractory disease include intensive supportive care, radiotherapy, bisphosphonates, second-line hormonal manipulations, cytotoxic chemotherapy and investigational agents. A post-treatment reduction in the level of prostate specific antigen (PSA) by 50% has been shown to correlate with survival and has been accepted by consensus as a valid endpoint in clinical trials. Chemotherapeutic agents such as mitoxantrone, estramustine, and the taxanes have yielded improved response rates and palliative benefit, but not improved survival. Therefore, current efforts must be focused on enrolling patients onto clinical trials of investigational agents with novel mechanisms of action, and on using survival, time to progression, and quality of life as end points in routine clinical practice.