Non-melanoma skin cancer is the most frequent type of cancer in humans. In this study we demonstrate that elevated IKK alpha expression in murine epidermis increases the malignancy potential of skin tumors. We describe the generation of transgenic mice overexpressing IKK alpha in the basal, proliferative layer of the epidermis and in the outer root sheath of hair follicles. The epidermis of K5-IKK alpha transgenic animals shows several alterations such as hyperproliferation, mislocalized expression of integrin-alpha 6 and downregulation of the tumor suppressor maspin. Treatment of the back skin of mice with the mitogenic agent 12-O-tetradecanoylphorbol-13-acetate causes in transgenic mice the appearance of different preneoplastic changes such as epidermal atypia with loss of cell polarity and altered epidermal tissue architecture, while in wild type littermates this treatment only leads to the development of benign epidermal hyperplasia. Moreover, in skin carcinogenesis assays, transgenic mice carrying active Ha-ras (K5-IKK alpha-Tg.AC mice) develop invasive tumors, instead of the benign papillomas arising in wild type-Tg-AC mice also bearing an active Ha-ras. Therefore we provide evidence for a tumor promoter role of IKK alpha in skin cancer, similarly to what occurs in other neoplasias, including hepatocarcinomas and breast, prostate and colorectal cancer. The altered expression of cyclin D1, maspin and integrin-alpha 6 in skin of transgenic mice provides, at least in part, the molecular bases for the increased malignant potential found in the K5-IKK alpha skin tumors.