For >50 years, the standard treatment for advanced prostate cancer has been hormonal therapy. However, all such treated patients eventually develop disease refractory to androgen suppression as manifested by increasing prostate-specific antigen (PSA) levels, progressive disease on radiographic imaging, and ultimately, symptomatic deterioration. Historical perceptions that treatment of hormone-refractory prostate cancer was a largely futile venture have faded over the past decade with the advances in new therapeutic strategies. With the use of PSA values to follow the progress of patients after definitive therapy, physicians are seeing more patients who have failed hormonal therapy yet have no symptoms from their disease. There are standard therapies available for patients who require palliation for symptoms, but there is no consensus on treatment for asymptomatic patients. To date, there has been no definitive increase in survival with any therapy in this group of patients. In addition, several novel drugs have advanced through preclinical testing into early clinical trials. It is these drugs--alone or in combination--that are designed to target strategic tumor pathways in these patients. This article will review a selection of agents that may be potentially useful in this population.