The serine/threonine protein kinase, Akt/PKB, has an essential function in cell survival during response to various stresses. Recent studies have demonstrated that Akt isoforms exhibit some distinct physiological functions, but the isotype-specific functions for Akt in the stress response have not been fully identified. In this study, we analysed the cellular response to genotoxic stress using isogenic wild-type, Akt1À/À and Akt2 À/À mouse embryonic fibroblasts (MEFs). Marked hypersensitivity of Akt2MEFs was observed to UV irradiation, whereas wild-type and Akt1À/À MEFs showed comparable levels of resistance. Akt2À/À mouse aortic endothelial cells also showed hypersensitivity to UV and the reconstitution of Akt2 expression in the Akt2 À/À MEFs restored the UV resistance of the cells. Interestingly, upon UV irradiation, JNK and p38 were significantly upregulated in Akt2MEFs, compared to wild-type and Akt1 À/À MEFs. Additionally, inhibition of JNK and p38 activation reduced UV-induced cell death. Furthermore, both the hyperactivation of JNK and p38 and the UV-induced cell death in Akt2 À/À MEFs were completely inhibited by restoring Akt2 expression. These results indicate that Akt2, but not Akt1, is essential for cell survival upon UV irradiation, and that Akt2 prevents UV-induced cell death by inhibiting activation of JNK and p38.