The epidermis is characterized by the continual turnover of its basic cellular unit, the keratinocyte. To determine whether genes known to regulate apoptosis could affect keratinocyte biology, transgenic mice overexpressing bcl-xL or bcl-xS under the control of the human keratin 14 promoter were generated. The maturation process and cellularity of the stratified epidermis were not compromised in the transgenic mice. Transgene function was demonstrated by enhanced cell survival of bcl-xL transgenic versus wild-type primary keratinocyte cultures treated with etoposide. To test the response of these mice to genotoxic damage, wild-type and transgenic mice were irradiated with UV light. The bcl-xL transgenic mice showed a dramatically increased resistance to irradiation, whereas the bcl-xS transgenic mice showed an increased sensitivity to irradiation. In contrast, neither transgene influenced the rate of would repair. Interestingly, endogenous Bcl-x was rapidly induced in keratinocytes adjacent to the would. Taken together, these findings demonstrate that although the terminal differentiation program is not altered by Bcl-x, acute stress responses within the skin can be influenced by regulators of apoptosis such as Bcl-x.