In recent years it became more and more evident that conserved embryonic signaling path-ways such as Hedgehog (Hh), Wingless (Wnt), and Notch play an important role in the devel-opment of human cancer. Especially, the hedgehog signaling pathway has moved into the focus for its ability to regulate pathologic processes including tumor growth, self-renewal, and resistance to chemotherapy. Preclinical data in various tumor types have proven the role of hedgehog signaling in cancers of the skin, brain, lung, breast, prostate, colon, as well as hematologic malignancies including leukemia, lymphoma, and multiple myeloma. Encouraged by these promising insights, several natural as well as designed compounds that regulate the hedgehog signaling pathway at different stages have been identified, but still, cyclopamine, the first inhibitor of the hedgehog pathway discovered plays a dominant role in ongoing research and as a lead in the development of clinical drug candidates. On the following pages, the story of cyclopamine and the hedgehog signaling pathway as well as the application of cyclopamine and congeners in the treatment of certain types of cancer and recent developments in the field of hedgehog modulation will be presented and discussed.