To investigate the function of Bcl‐x_L in the skin, we established keratinocyte‐specific Bcl‐x gene‐targeted mice under the keratin 5 promoter (K5). K5.Bcl‐x_L– / – mice were viable, devoid of alteration in the development of skin or appendages. However, they harbored spontaneous apoptotic keratinocytes in the epidermis. Bcl‐x_L‐deficient keratinocytes cultured in vitro readily underwent apoptosis in the absence of growth factors, but the addition of HGF or EGF resulted in restoration of cell survival, which was reversed by treatment with wortmannin, an inhibitor of phosphoinositide‐3 kinase (PI3K). Topical treatment of K5.Bcl‐x_L− / − mice with wortmannin sensitized the skin for apoptosis induced by UV (UV) B, although wild‐type epidermis was only marginally affected by this treatment, suggesting that the resistance to UVB largely depended on PI3K‐Akt signaling in Bcl‐x_L‐deficient mice but not in wild‐type mice. Furthermore, UVB irradiation resulted in redistribution of phosphorylated Akt from the basal layer to the suprabasal layer, indicating that Akt could spatially cooperate with Bcl‐xL upon UVB exposure in the upper epidermis where Bcl‐x_L is normally localized. These results suggest that Bcl‐x_L and the PI3K‐Akt pathway form a cooperative, intercompensatory axis for the protection of epidermal keratinocytes from apoptosis in vivo.