The p73 protein, a member of the p53 family, has both developmental and tumorigenic functions. Here we show that p73 is cleaved by caspase-3 and -8 both in vitro and in vivo during apoptosis elicited by DNA-damaging drugs and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor ligation. TAp73 and some of its cleavage products are localized to mitochondria. siRNA-mediated downregulation of p73 expression induced a small but significant change in the susceptibility of HCT116 cells to TRAIL-induced apoptosis. A transcription-deficient mutant of TAp73 enhanced TRAIL-induced apoptosis suggesting that p73 protein has transcription-independent functions during death receptor-mediated apoptosis. Additionally, recombinant p73 protein induced cytochrome c release from isolated mitochondria providing evidence that nonnuclear p73 may have additional functions in the progression of apoptosis.