The p53 tumor suppressor promotes cell cycle arrest or apoptosis in response to diverse stress stimuli. p53-mediated cell death depends in large part on transcriptional up-regulation of target genes. One of these targets, P53-induced protein with a death domain (PIDD), was shown to function as a mediator of p53-dependent apoptosis. Here we show that PIDD is a cytoplasmic protein, and that PIDD-induced apoptosis and growth suppression in embryonic fibroblasts depend on the adaptor protein receptor-interacting protein (RIP)-associated ICH-1/CED-3 homologous protein with a death domain (RAIDD). We provide evidence that PIDD-induced cell death is associated with the early activation of caspase-2 and later activation of caspase-3 and -7. Our results also show that caspase-2(-/-), in contrast to RAIDD(-/-), mouse embryonic fibroblasts, are only partially resistant to PIDD. Our findings suggest that caspase-2 contributes to PIDD-mediated cell death, but that it is not the sole effector of this pathway.