The mouse skin model of multistage carcinogenesis continues to serve as a major in vivo model for studying the sequential and stepwise evolution of the cancer process by chemical and physical carcinogens. The initiation stage of mouse skin carcinogenesis involves genetic damage in the form of DNA adducts or initiator-induced DNA base changes. These changes ultimately lead to mutations in critical target genes of epidermal stem cells. The rasHa gene, and to a limited extent the N-ras gene, have been identified as target genes for certain tumor initiators in this model system (reviewed in DiGiovanni 1992). The promotion stage of mouse skin carcinogenesis involves the production and maintenance of a chronic state of hyperplasia and cell proliferation and ultimately the selective clonal expansion of initiated cells. The hallmark of all tumor promoters that have been adequately tested is their ability to induce a potentiated hyperplasia after several treatments that is greater than that observed after a single application. Tumor promoters produce many effects when applied topically to mouse skin. Many of the effects that occur after a single application of phorbol esters such as TPA appear to be mediated by its interaction with PKC (Nishizuka 1989). An important question is whether the activation of PKC per se is responsible for tumor promotion by TPA. Because repetitive treatments with TPA lead to a sustained loss of PKC, it is possible that other effects not mediated by PKC but produced by phorbol esters and related compounds may play an important role in the production and maintenance of chronic hyperplasia and cell proliferation in the skin and for skin tumor promotion. More attention should be placed on studying the promoting actions of other compounds outside of the most commonly studied phorbol esters. Investigations of some of these compounds already have and will continue to provide important clues regarding possible common pathways shared by diverse promoting agents. One such pathway may involve the EGFr and its ligand TGF alpha. As discussed in this review, it is now evident that many different types of promoting agents increase production of TGF alpha (Ellem et al. 1988, Pittelkow et al. 1989, Choi et al. 1991, Imamoto et al. 1991, J. DiGiovanni unpublished studies). Although many tumor promoters initially decrease the binding of 125I-EGF to EGFr in specific cell types, including mouse epidermal cells, the long-term effects of tumor promoters, especially after repetitive treatments, may be considerably different.+4