The causal link between uncontrolled Hedgehog (Hh) pathway activation and oncogenesis has inspired the development of small-molecule inhibitors of this developmental signaling pathway. In this chapter, we discuss how a cyclopia-inducing natural product isolated in the 1950s has engendered a pharmacopoeia of compounds that block Hh target gene expression. We describe how these Hh pathway inhibitors were discovered, their mechanisms of action, and their potential as anti-cancer agents. We also examine potential limitations of current approaches and future directions for Hh pathway-targeting chemotherapies.