S100A2 is generally found expressed in the epidermis and was recently shown to play a crucial role in the differentiation of keratinocytes. Also known as CaN19, S100A2 was identified as a potential tumor suppressor. Expression of S100A2 is upregulated by p53. The proteins p63 and p73 are related to p53 and are expressed as several splice variants with partially overlapping tasks but also functions different from p53. It had been shown that p63 proteins with mutations in their DNA-binding domain cause severe phenotypes in man as autosomal dominantly inherited disease including EEC, AEC, SHFM, LMS and ADULT syndromes. Here we show that S100A2 is a transcriptional target of p63/p73 family members, particularly the p63 splice variant TAp63gamma. The regulation is mediated by a novel transcriptional element in the S100A2 promoter which is bound by TAp63gamma but not by p53. Mutant p63 proteins derived from EEC and ADULT syndrome patients cannot activate S100A2 transcription whereas SHFM-related mutants still can stimulate the S100A2 promoter. Consistent with a function in tumor suppression S100A2 expression is stimulated upon DNA damage. After doxorubicin treatment p63gamma proteins are recruited to the S100A2 promoter in vivo. This may indicate a function of the p63-dependent S100A2 regulation in tumor suppression.