c-Myc overexpression has been associated with several types of human cancers. To study the role of c-myc in epidermal differentiation and carcinogenesis, a transgenic mouse model was created to overexpress c-Myc in the epidermis. Human c-myc 2 cDNA was subcloned into a 6.5 kb mouse loricrin expression vector, ML.myc2. This loricrin promoter primarily directs expression in the epidermis in both proliferating and differentiated keratinocytes. On day 4, ML.myc2 transgenic pups develop a hyperkeratotic phenotype, which progressively worsens until day 7. Upon histological analysis, both hyperplasia and hyperkeratosis were evident. Bromodeoxyuridine (BrdU) incorporation revealed that transgenic mice had a threefold increase in the number of proliferating cells as compared with a normal littermate. Proliferative cells in the ML.myc2 epidermis were also found to be suprabasal, suggesting an inhibition of terminal differentiation in keratinocytes. Inhibition of terminal differentiation by c-Myc overexpression was further suggested by aberrant expression of differentiation markers, keratin 1, keratin 6, loricrin, and filaggrin in ML.myc2 transgenic mice. Interestingly, ML.myc2 keratinocytes exhibit a reduced sensitivity to UV-B induced apoptosis, in vivo. In vitro studies reveal the reduced sensitivity of ML.myc2 keratinocytes to UV-B irradiation is growth factor dependent. These findings provide evidence that overexpression of c-Myc in the epidermis induces proliferation, inhibits terminal differentiation and decreases the sensitivity of keratinocytes to UV-B induced apoptosis.