The keratin cytoskeleton is formed in different epidermal compartments by distinct polypeptides. Basal, proliferative keratinocytes express keratin (K) 5 and K14, whereas, suprabasal, post-mitotic keratinocytes express K1 and K10. Changes in this keratin pattern have been found to occur in hyperproliferative skin disorders and, in particular, throughout mouse epidermal carcinogenesis. Whereas some keratins not found in normal epidermis (K6, K16, K13, and K8) are induced at different stages of tumor development, K1 and K10 expression is lost. To determine whether K1 and K10 loss is just a consequence of the altered differentiation program or an event required for tumor progression, we generated transgenic mice carrying the human keratin 10 gene (hK10) under the control of a bovine keratin 6 gene regulatory region, which is silent in normal skin but is induced and drives transgene expression in hyperproliferative skin keratinocytes and, therefore, in skin tumors. Transgenic animals subjected to a complete carcinogenesis protocol developed tumors that contained various amounts of transgenic hK10. Although no significant difference was found in tumor number or malignancy, tumor onset was significantly delayed in transgenic mice, indicating that the presence of K10 actually impairs tumor development.