The p53 transcriptional network is composed of hundreds of effector genes involved in varied stress-response pathways, including cell cycle arrest and apoptosis. It is not clear how distinct p53 target genes are differentially activated to trigger stress-specific biological responses. We analyzed the p53 transcriptional program upon activation by two DNA-damaging agents, UVC and doxorubicin, versus the non-genotoxic molecule Nutlin-3. In colorectal cancer cells, UVC triggers apoptosis, doxorubicin induces transient cell cycle arrest followed by apoptosis, and Nutlin-3 leads to cell cycle arrest with no significant apoptosis. Quantitative gene expression analysis allowed us to group p53 target genes into three main classes according to their activation profiles in each scenario. The CDK-inhibitor p21 was classified as a Class I gene, being significantly activated under cell cycle arrest conditions (i.e. doxorubicin and Nutlin-3) but not during UVC-induced apoptosis. Chromatin immunoprecipitation analysis of the p21 locus indicates that the level of p53-dependent transcription is determined by the effects of stimulus-specific transcriptional coregulators acting downstream of p53 binding and histone acetylation. In particular, our analysis indicates that the subunits of the CDK-module of the human Mediator complex function as stimulus-specific positive coregulators of p21 transcription.