The process of stratified epithelial development depends upon a transcriptional program directed by the p53-related transcription factor p63. p63 is required for the commitment of the ectoderm to stratification and for the completion of terminal differentiation in stratified epithelia, and mutations in p63 have been identified in multiple developmental disorders affecting ectoderm-derived tissues. Recent work from our laboratory has determined that the p53 target gene Perp is required for the integrity of the stratified epithelia specified by p63, and that expression of Perp in these structures depends on the presence of p63. In these tissues, Perp is a critical component of the desmosome, a cell-cell adhesion complex whose constituents are frequently mutated in human diseases affecting the skin and hair. Perp's position downstream of p63 and p53, as well as its essential role in normal desmosome function, suggest that it, like other adhesion proteins, may be a target for mutation in human blistering diseases or cancer.