TGFβs are thought to have tumor suppressor activity in many organ systems, but receptor inactivation in mouse models has not previously resulted in increased spontaneous tumorigenesis. A study in this issue of Cancer Cell shows that mice with a targeted knockout of the type II TGFβ receptor in stratified epithelia specifically develop spontaneous squamous cell carcinomas in the anogenital region, but not in the skin. Loss of TGFβ signaling appears to destabilize the epithelium such that homeostasis fails in the face of persistent proliferative challenge, a normal feature of the anogenital site, and latent invasive and migratory phenotypes are unmasked.