PTEN is a dual protein ; lipid phosphatase and hereditary heterozygous mutation of PTEN is associated in humans with Cowden disease, a rare autosomal dominant familial syndrome with a high risk of developing benign and malignant tumors in many organ systems. To investigate the role of PTEN in skin development and oncogenesis, we used the Cre-loxP system to generate a keratinocyte-specific null mutation of Pten in mice (k5Ptenflox/flox mice). k5Ptenflox/flox mice exhibit wrinkled skin as the result of epidermal hyperplasia and hyperkeratosis and ruffled, shaggy, and curly hair. Histological examination revealed that skin morphogenesis is accelerated in k5Ptenflox/flox mice. All k5Ptenflox/flox mice develop spontaneous tumors within 8.5 months of birth. PTEN is thus an essential regulator of normal homeostasis and oncogenesis in the skin.