Integrin-mediated cell adhesion and signaling events are essential for the proper development and homeostasis of most epithelial tissues. Dysregulation of integrin expression and function can cause abnormal epithelial cell proliferation and/or differentiation, contributing to the pathogenesis of malignant epithelial cancers. Here we report on the use of a conditional knockout strategy exploiting the Cre/Lox technology to study the in vivo functions of alphav integrins during epithelial cell proliferation and differentiation. We show that genetic ablation of alphav integrin expression in basal epithelial cells of the eyelid skin and conjunctiva causes the formation of tumors that are strikingly similar to the malignant epithelial cancer, squamous cell carcinoma. These data suggest a mechanism whereby alphav integrins normally suppress epithelial cell proliferation, likely via adhesion to ECM ligands, as well as by the modulation of intracellular signaling cascades. We propose that alphav gene deletion eliminates normal integrin-mediated growth suppression, ultimately leading to cellular transformation and tumorigenesis. Hence, these studies reveal a novel tumor suppressor-like function of alphav integrins and provide a genetically tractable mouse model for studying the pathogenesis of squamous cell carcinoma and related cancers of epithelial origin, as well as to test and develop novel therapeutic compounds to treat or prevent squamous cell carcinoma of the skin.