The p53 family member p63 plays an essential role in the developing epithelium, and overexpression of the ΔNp63a isoform is frequently observed in human squamous cell carcinomas (SCCs). These findings have suggested that ΔNp63a might function as an oncogene within squamous epithelial cells. Nevertheless, the mechanism by which ΔNp63a might promote tumorigenesis remains poorly understood, and data from mouse models implies that the p63 locus might in fact function as a tumor suppressor in these same tissues. A recent study using RNA interference in human SCC-derived cell lines shows that ΔNp63a mediates an essential survival function in human SCC cells by virtue of its ability to suppress the pro-apoptotic function of the related p53 family member p73. These findings support an oncogenic role for ΔNp63a and they demonstrate the existence of critical physical and functional interactions between endogenous p53 family members in human cancer. Specific chemotherapeutic agents and future targeted approaches may be able to exploit this pathway to therapeutic advantage.