Unlike its family member p53, TP63 is rarely mutated in human cancer. However, ΔNp63α protein levels are often elevated in tumors of epithelial origin, such as squamous cell carcinoma and cholangiocarcinoma. To study the oncogenic properties of ΔNp63α in vivo, we generated transgenic mice overexpressing ΔNp63α from the Rosa26 locus promoter controlled by keratin 5-Cre. We found that these mice spontaneously develop epidermal cysts and ectopic ΔNp63α expression in the bile duct epithelium that leads to dilatation of the intrahepatic biliary ducts, to hepatic cyst formation and bile duct adenoma. Moreover, when subjected to models of 7,12-dimethylbenz[a]anthracene-based carcinogenesis, tumor initiation was increased in ΔNp63α transgenic mice in a gene dosage-dependent manner although ΔNp63α overexpression did not alter the sensitivity to 7,12-dimethylbenz[a]anthracene-induced cytotoxicity in vivo. However, keratinocytes isolated from ΔNp63α transgenic mice displayed increased survival and delayed cellular senescence compared with wild-type keratinocytes, marked by decreased p16Ink4a and p19Arf expression. Taken together, we show that increased ΔNp63α protein levels facilitate oncogenic transformation in the epidermis as well as in the bile duct.