Mice of the C57BL/6 strain are resistant to the development of skin squamous carcinomas (SCCs) induced by an activated Ras oncogene, whereas FVB/N mice are highly susceptible1. The genetic basis of this difference in phenotype is unknown. Here we show that susceptibility to SCC is under the control of a carboxy-terminal polymorphism in the mousePtchgene. F1hybrids between C57BL/6 and FVB/N strains ((B6FVB)F1) are resistant to Ras-induced SCCs, but resistance can be overcome either by elimination of the C57BL/6Ptchallele (PtchB6) or by overexpression of the FVB/NPtchallele (PtchFVB) in the epidermis ofK5Hras-transgenic (B6FVB)F1hybrid mice. The humanPatched(PTCH) gene is a classical tumour suppressor gene for basal cell carcinomas and medulloblastomas, the loss of which causes increased signalling through theSonic Hedgehog(SHH) pathway2-5. SCCs that develop inPtchB6+/−mice do not lose the wild-typePtchgene or show evidence of increased SHH signalling. AlthoughPtchFVBoverexpression can promote SCC formation, continued expression is not required for tumour maintenance, suggesting a role at an early stage of tumour cell lineage commitment. ThePtchpolymorphism affects Hras-induced apoptosis, and binding to Tid1, the mouse homologue of theDrosophila l(2)tidtumour suppressor gene. We propose thatPtchoccupies a critical niche in determining basal or squamous cell lineage, and that both tumour types can arise from the same target cell depending on carcinogen exposure and host genetic background.