Differential expression of p53 isoforms might participate in the marked resistance towards conventional chemotherapy of renal cell carcinomas (RCCs). Therefore, we analysed their differential expression and regulation in RCCs. RCCs expressed a more p53 activating isoform pattern during tumor initiation and progression, in vivo. In vitro, two cell lines exhibiting a similar sensitivity towards Topotecan-induced cell death revealed a similar induction of p53 target genes but strongly differed in their extent of apoptosis. Furthermore, they strongly differed in their basal expression patterns and differential regulation of the isoforms. In conclusion, our study examined for the first time the differential expression and regulation of all p53 isoforms in a tumor in vivo. Furthermore, novel results in our in vitro studies show that p53 isoforms are strongly differentially regulated by chemotherapy in RCCs and that expression and regulation of so-called "p53-target genes" are obviously at least in part regulated by other transcription factors. In addition, our original findings show that p53 isoform expression in RCC cell lines is of minor importance for sensitivity towards chemotherapy.