p63 is a member of a gene family also including the p53 tumor suppressor and p73. In contrast to p53, p63 is rarely mutated in human cancers. Rather, gene amplification and dysregulated expression of p63 protein have been observed, particularly in squamous cell carcinomas. p63 is essential for development of stratified squamous epithelium, including the epidermis. The p63 gene is expressed as multiple protein isoforms with different functional capacities, and the balance of these isoforms, along with the presence or absence of the other family members, p53 and p73, can impact biological outcome. Both gene silencing and overexpression approaches have been utilized to elucidate the contributions of specific p63 isoforms to normal epidermal morphogenesis and tissue maintenance. While numerous studies have established the essential nature of p63 in the epidermis, the basis of this requirement, and the unique, as well as, overlapping functions of the individual isoforms, remain controversial. In this review, we summarize the current understanding of roles played by specific p63 isoforms within the context of epidermal morphogenesis and homeostasis of the established epidermis, and the potential impact of p63 dysregulation on cancer development.