Genes that are active during normal development are frequently reactivated during neoplastic transformation. We now report that developmentally expressed TAp63 isoforms are frequently reactivated in human squamous cell carcinomas. To determine the consequences of TAp63 reactivation, we induced TAp63α expression during chemically-induced skin carcinogenesis. Deregulated TAp63α expression dramatically accelerated tumor development and progression, frequently resulting in epithelial-mesenchymal transitions to spindle cell carcinomas and lung metastases. Consistent with this observation, we detected high levels of Twist and N-cadherin in tumors overexpressing TAp63α. Thus, as observed for other developmental pathways, aberrant reactivation of TAp63 predisposes to tumor development and progression. (Cancer Res 2006; 66(8): 3981-6)