To define the role of TGFa in normal tissue function and in pathogenesis, transgenic mice have been generated bearing a fusion gene consisting of the mouse metallothionein 1 promoter and a human TGFa cDNA. In these mice, human TGFa RNA and protein are abundant in many tissues and TGFa is detectable in blood and urine. The effects of TGFa overproduction in transgenie mice are pleiotropic and tissue specific. The liver frequently contains multifocal, well-differentiated hepatocellular carcinomas that express enhanced levels of human TGFa RNA. The mammary gland exhibits impeded morphogenetic penetration of epithelial duct cells into the stromal fat pad. The pancreas shows progressive interstitial fibrosis and a florid acinoductular metaplasia, during which acinar cells appear to degranulate, dedlfferentiate, and assume characterlstics of intercalated or centroacinar duct cells. TGFa therefore plays an important role in cellular proliferation, organogenesis, and neoplastic transformation.