The hedgehog (Hh) signaling pathway, which is almost completely silenced in normal adult tissues but highly activated in cancer, offers ideal drug targets for small molecule development. During the last few years, several studies have indicated that the Hh pathway plays a role in tumor development and maintenance, and novel drugs inhibiting Hh signaling have been discovered. Although results from clinical trials in patients harboring activating mutations of Hh have been promising, there are many controversies regarding the role of the pathway in tumors that demonstrate ligand over-expression without identified mutations. In this review, we focus on the function and expression of the Hh pathway in different tumors and discuss the targeting approaches tested in preclinical and clinical studies.