Prostate cancer is the most common malignancy and the second leading cancer-related cause of death in men in the USA. Despite enormous efforts in understanding the molecular basis of prostate cancer, very little progress has been made in prevention and treatment of this often lethal cancer. Recent studies have demonstrated that hedgehog signaling is frequently activated in advanced or metastatic prostate cancers. With small molecule inhibitors available to analyze the hedgehog signaling pathway, a novel rationale for prostate cancer therapy can be devised.