Ligand-dependent and ligand-independent activation of the Hedgehog (Hh) signaling pathway is involved in tumorigenesis. The importance of mutations in Hh pathway components leading to constitutive signaling has been well established in basal cell carcinoma and medulloblastoma. However, the role of ligand-driven Hh pathway activation in cancer remains to be established. Three recent articles support a model in which, in the absence of mutations in the Hh pathway, Hh ligands expressed by a subset of epithelial cancers, including colon, pancreatic, and ovarian cancer, promote tumor growth indirectly by activating Hh signaling in the surrounding stroma, which, in turn, provides a more favorable environment for tumor growth. These data have important implications for the use of Hh pathway inhibitors currently in development and for selection of tumors likely to respond to such inhibitors. [Cancer Res 2009;69(15):6007–10]