p63, a member of the p53 gene family, known to play a role in development, has more recently also been implicated in cancer progression. Mice lacking p63 exhibit severe developmental defects such as limb truncations, abnormal skin, and absence of hair follicles, teeth, and mammary glands. Germline missense mutations of p63 have been shown to be responsible for several human developmental syndromes including SHFM, EEC and ADULT syndromes and are associated with anomalies in the development of organs of epithelial origin. The contrasting phenotypes associated with the different classes of p63 mutations might be in part due to the differential regulation of target genes. A previous report has demonstrated that heterozygous p63 mutations display high predisposition to tumor formation. Moreover, it has been shown that both p63 and p73, another member of the p53 family, are required for p53 mediated DNA damage induced apoptosis. Finally, differential splicing of p63 gene gives rise to p63 isoforms which can either act as tumor suppressors or oncogenes. The goal of this study is to determine the effects of naturally occurring TAp63γ mutants on regulation of p53/p63 and p63 specific target genes and their effects on global gene expression. Our results indicate that both TAp63γ(R227Q) and TAp63γ(R298Q) mutants mimic wildtype TAp63γ effects on its target genes. TAp63γ(K194E) and TAp63γ(R280C) significantly induced genes regulated by p63 and p53, but not those specific for p63. TAp63γ(R279H) andTAp63γ(R204W) were unable to induce any of the targets tested in this study. Co-transfection of p63 mutants along with wildtype p63 was performed to assess the effects of p63 mutants on ability of wildtype p63 to induce its target genes, while co-transfection of TAp63γ(R279H) and TAp63γ(R204W) led to a complete inhibition of the wildtype TAp63γ mediated induction of p63 specific target genes, they had no effect on p53/p63 target genes. We demonstrated that the ability of these mutants to regulate wildtype activity was independent of their ability to either interact with wildtype TAp63γ or affect its localization. In addition, we demonstrated that the effects of these mutants on cell growth and survival were consistent with their ability to regulate the downstream targets when compared to wildtype TAp63γ. Furthermore, our analysis of the GeneChip data using GeneSpring led to the identification of several common and unique genes regulated by specific p63 mutants when compared to cells transfected with wildtype p63. Additionally, the specific genes regulated by the p63 mutants observed in EEC, SHFM and ADULT syndrome might offer unique insights in understanding the involvement of p63 in development, ectodermal-mesenchymal interactions and differentiation. In summary, we show that p63 mutants exhibit a differential effect on p63 specific and p53/p63 specific target genes and on induction of apoptosis. This, in turn might have a significant impact on p63 mutation associated abnormalities of human developmental syndromes. Taken together, our data shows that p63 mutants differentially regulate gene expression and provide an insight into the molecular biology of p63. Further, these results will aid in better understanding of role of p63 mutants in development and cancer.