IKK (I kappaB kinase) alpha is essential for embryonic skin development in mice. Mice deficient in IKKalpha display markedly hyperplasic epidermis that lacks terminal differentiation, and they die because of this severely impaired skin. However, the function of IKKalpha in human skin diseases remains largely unknown. To shed light on the role of IKKalpha in human skin diseases, we examined IKKalpha expression and Ikkalpha mutations in human squamous cell carcinomas (SCCs). We found a marked reduction in IKKalpha expression in poorly differentiated human SCCs and identified Ikkalpha mutations in exon 15 of Ikkalpha in eight of nine human SCCs, implying that IKKalpha is involved in development of this human skin cancer. Furthermore, in a chemical carcinogen-induced skin carcinogenesis setting, mice overexpressing human IKKalpha in the epidermis under the control of a truncated loricrin promoter developed significantly fewer SCCs and metastases than did wild-type mice. The IKKalpha transgene altered the skin microenvironment conditions, leading to elevated terminal differentiation in the epidermis, reduced mitogenic activity in the epidermis, and decreased angiogenic activity in the skin stroma. Thus, overexpression of IKKalpha in the epidermis antagonized chemical carcinogen-induced mitogenic and angiogenic activities, repressing tumor progression and metastases.