In order to study skin tumor promotion, a cell culture model system analogous to initiated mouse epidermis was developed. Keratinocytes of the neoplastic cell line 308 display the initiated phenotype since papillomas are produced when the cells are grafted to the backs of athymic mice. Coculture of a small number of these initiated cells with confluent normal keratinocytes results in the suppression of growth of colonies of 308 cells. This inhibition, which is calcium dependent, epidermal cell specific, and requires cell contact, can be overcome by exposure to various tumor promoters. Promoters and antipromoters of diverse structure and mechanism of action are recognized in this keratinocyte coculture model.