The Hedgehog (Hh) pathway is a developmental signaling pathway involved in numerous developmental processes, including determination of cell fate, patterning, proliferation, survival, and differentiation. While this pathway is silenced in most adult tissues, aberrant activation of it has been documented in a variety of malignancies. In cancers such as basal cell carcinoma (BCC), ligand-independent mechanisms lead to constitutive Hh pathway activation through mutations in components of the pathway, including patched-1 (PTCH1) or smoothened (SMO). On the contrary, numerous other solid and hematologic tumors have been shown to harbor ligand-dependent activation of the Hh pathway by autocrine or paracrine mechanisms. Given that aberrant Hh pathway signaling has been seen in a number of malignancies, this pathway has been an attractive target for drug development. While the best-characterized approach is to target the SMO receptor, other rational approaches for inhibiting the Hh pathway include inhibiting downstream components or directly binding Hh ligands. In January of 2012, vismodegib, a SMO antagonist, became the first agent to target the Hh pathway to receive approval by the United States Food and Drug Administration (FDA) after this agent showed remarkable activity in phase I and II trials for the treatment of BCC. Despite promising preclinical studies with Hh pathway inhibitors in other malignancies that have suggested a potential role for these agents, attempts to translate this potential to clinical benefit has been disappointing. Future efforts will require further careful interpretation and analysis to determine the potential determinants and predictors of efficacy. Currently, several phase I and II trials evaluating Hh inhibitors in a variety of tumor settings are underway.