The transcription factor p63 is a homologue of the tumor suppressor p53. Unlike p53, which is dispensable for normal development, p63 is critical for the development of stratified epithelial tissues such as epidermis, breast, and prostate. p63 encodes multiple protein isoforms with both transactivating and transcriptional repressor activities that can regulate a wide spectrum of target genes. p63 is also implicated in tumor formation and progression in stratified epithelia, with evidence for both tumor suppressive and oncogenic properties. This review will examine current data and hypotheses regarding the role of p63 in the development, maintenance, and tumorigenesis of stratified epithelium.