Transgenic mice were developed to study the role of c‐src in epithelial tumorigenesis through targeted expression of a constitutively active form of murine c‐src (src⁵²⁹). Src⁵²⁹ was targeted to the interfollicular epidermis with the human keratin 1 (HK1) promoter. The skin phenotype of these mice was characterized by exaggerated epidermal hyperplasia and hyperkeratosis within the first week after birth. The severity of this phenotype correlated with overall src kinase activity, both of which subsided with age. Treatment of adult HK1.src⁵²⁹ transgenic mice with the phorbol ester tumor promoter 12‐O‐tetradecanoylphorbol‐13‐acetate resulted in an increase in epidermal hyperplasia and labeling index significantly greater than that seen in nontransgenic littermates. In addition, HK1.src⁵²⁹ transgenic mice developed papillomas earlier and in significantly greater numbers compared with nontransgenic littermates in a standard initiation‐promotion experiment. The data support the hypothesis that activation of c‐src kinase plays a role in skin tumor promotion. © 2002 Wiley‐Liss, Inc.