The role of apoptosis in the pathogenesis of skin cancer was analyzed in mice bearing a Bcl-x_l transgene expressed under the control of the keratin 14 promoter. No spontaneous tumors developed in the skin of these transgenic mice. Bcl-x_l transgenics also failed to develop skin lesions following treatment with the chemical mutagen 9,10-dimethyl-1,2-benzanthracene, or the tumor promoter O-tetradecanoylphorbol-13-acetate. However, Bcl-x_l transgenics developed a two-fold greater number of benign papillomas than control littermates following treatment with the combination of 9,10-dimethyl-1,2-benzanthracene and O-tetradecanoyl-phorbol-13-acetate. More significantly, Bcl-x_l transgenic mice developed invasive squamous cell carcinoma earlier and more frequently than wild-type controls in response to the chemical agents. These data suggest that Bcl-x_l cannot functionally substitute for a mutagenic initiator or mitogenic promoter in tumorigenesis. In contrast, Bcl-x_l overexpression can dramatically increase the malignant conversion rate of benign tumors, suggesting that inhibition of apoptosis can contribute to tumor progression.