Inappropriate α6β4 integrin expression correlates with a high risk of tumour progression in stratified squamous epithelia. Targeted expression of α6β4 in the suprabasal layers of transgenic mouse epidermis dramatically increased the frequency of papillomas, carcinomas and metastases induced by chemical carcinogenesis, independent of the β4 cytoplasmic domain. Suprabasal α6β4 also perturbed transforming growth factor β (TGFβ) signalling as demonstrated by decreased nuclear Smad2 in transgenic epidermis and tumours. In cultured keratinocytes, suprabasal α6β4 relieved TGFβ-mediated growth inhibition and blocked nuclear translocation of activated Smad2/3. Responsiveness to TGFβ could be restored by inhibiting cadherin-mediated cell-cell adhesion or phosphoinositide 3-kinase (PI3-K) activity, but not by inhibiting mitogen-activated protein kinase (MAPK) activity. These data suggest that suprabasal α6β4 promotes tumourigenesis by preventing TGFβ from suppressing clonal expansion of initiated cells in the epidermal basal layer.