The β-catenin/TCF signaling pathway is essential for the maintenance of epithelial stem cells in the small intestine 1. c-Myc a downstream target of β-catenin/TCF (ref. 2), can induce differentiation of epidermal stem cells in vitro 3. To determine the role of c-Myc in epidermal stem cells in vivo, we have targeted expression of human MYC2 to the hair follicles and the basal layer of mouse epidermis using a keratin 14 vector (K14. MYC2). Adult K14. MYC2 mice gradually lose their hair and develop spontaneous ulcerated lesions due to a severe impairment in wound healing; their keratinocytes show impaired migration in response to wounding. The expression of β1 integrin, which is preferentially expressed in epidermal stem cells 4 is unusually low in the epidermis of K14. MYC2 mice. Label-retaining analysis to identify epidermal stem cells reveals a 75% reduction in the number of stem cells in 3-month-old K14. MYC2 mice, compared with wildtype mice. We conclude that deregulated expression of c-Myc in stem cells reduces β1 integrin expression, which is essential to both keratinocyte migration and stem cell maintenance.