p63 plays an important role in skin and limb development. This has been clearly demonstrated using mouse models and from studies on human patients harboring p63 mutations. One question that remains unanswered is whether p63 is a tumor suppressor gene or an oncogene. The complexity of the study of p63 is due to the existence of multiple isoforms with opposing functions. The lack of antibodies that distinguish between these isoforms has made the ability to analyze the expression of p63 difficult in human tumors. Many studies have found that p63 is overexpressed in human tumors while other studies have shown a loss of expression of p63. Here, we review the roles of p63 in tumor development and suppression in mouse models and human tumors.