Epidermal morphogenesis is a complex process that culminates in the formation of a barrier that protects the organism from environmental substances and dehydration. p63, a transcription factor, is essential for normal epidermal morphogenesis as demonstrated by the failure of mice lacking p63 expression to develop an epidermis. However, since two independently generated p63(-/-) mouse models displayed different phenotypes, the role of p63 in epidermal morphogenesis has remained controversial. Furthermore, the tumor susceptibility phenotypes of both p63(-/-) mouse models were strikingly different. In this review, we discuss these conflicting findings and provide evidence for various roles of p63 in the epidermis under normal and pathological conditions.