The transcriptional programs triggered by p53 during tumor suppression and in response to DNA damage remain to be clarified. Using whole genome mapping of p53 binding and gene expression profiling, we investigated the transcriptional circuitry induced by p53 in suppressing cancer development and in response to genotoxic injury. We studied the progression of Myc-induced lymphomas in Eμ-myc transgenic mice, as well as the regression of these lymphomas following restoration of p53 function, by either pharmacological or genetic means. In parallel, we determined the p53-dependent transcriptional program in splenic cells from mice exposed to ionizing radiation. We thus expanded our understanding of the p53 response to oncogenic and genotoxic stress and identified a set of novel components of the p53 transcriptional program. Currently, we are testing the impact of these new p53 target genes on tumorigenesis using an RNA interference (RNAi)-based functional genetic screen. Altogether our data represent an extensive characterization of the p53-regulated network in response to different stimuli and will hopefully highlight new tumor suppressive mechanisms, paving the way for their therapeutic application.