The Hedgehog-Gli (Hh-Gli) signaling pathway controls many aspects of tissue patterning, cell proliferation, differentiation and regeneration and regulates cell number in various organs. In adults, the Hh-Gli pathway remains active in a number of stem cells and regenerating tissues. Inappropriate and uncontrolled HH-GLI pathway activation has been demonstrated in a variety of human cancers. Three recent papers show that components of the pathway are expressed in human prostate tumors and, more importantly, that prostate cancers depend on sustained HH-GLI signaling. These data raise the possibility of a new therapeutic approach to treat this often lethal disease.