Yauch and colleagues [38] made the interesting observation that Smo-antagonist-mediated growth inhibition of a large number of cancer cell lines of epithelial origin does not correlate with Hh target gene expression in these cells, suggesting that a) the observed in vitro growth repression might be due to off-target effects when these compounds are used at high concentrations, and b) there is a paracrine requirement for Hh ligand signaling in the tumorigenesis of Hh-expressing cancers, with important implications for the development of Hh pathway antagonists in cancer. This evidence concerns the gene SMO and cancer.