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.