p63 is a recently characterized p53-homolog that is consistently expressed by basal/somatic stem cells of stratified epithelia, myoepithelial cells of the breast and salivary glands, and proliferative compartment of gastric mucosa. p63 is located on the long arm of chromosome 3 (3q27) and it encodes six isoforms, three transactivating (TA) and three DeltaN-isoforms. While the first three isoforms may act as tumor suppressor genes, the DeltaN-isoforms may inhibit the p53/TA-p63-driven cell cycle arrest and apoptosis. Recently, the putative applications of p63 in the identification of myoepithelial cells of the breast and basal cells of the prostate acini have been evaluated; however, no critical systematic analysis of its role in surgical pathology practice have hitherto been reported. We review the putative roles of p63 in surgical pathology practice and provide guidelines for future directions on p63 translational research.