Discovery of the p53 homologs p63 and p73 has brought new excitement to the p53 field. Identification of homologous genes coding for several proteins with similar and antagonistic properties towards p53 has been both intriguing and perplexing. A multitude of properties have been attributed to these new homologs and this review will focus on the biochemical and biological aspects of one family member, p63. Although the most ancient member of the p53 family, p63 is the most recently discovered and the least is known about this family member. Unlike p53, whose protein expression is not readily detectable in epithelial cells unless they are exposed to various stress conditions, p63 is expressed in select epithelial cells at high levels under normal conditions. p63 is highly expressed in embryonic ectoderm and in the nuclei of basal regenerative cells of many epithelial tissues in the adult including skin, breast myoepithelium, oral epithelium, prostate and urothelia. In contrast to the tumor suppressive function of p53, over-expression of select p63 splice variants is observed in many squamous carcinomas suggesting that p63 may act as an oncogene. Undoubtedly, the biochemical and biological activities attributed to p63 over the next several years will be diverse and regulation of the p63 gene and its several protein products complex. The use of various model systems and the study of human disease should continue to lead to rapid advances in our understanding of the role of p63 in development, epithelial cell maintenance and tumorigenesis.