Similarly to p53, p73α and p73β induce growth arrest and/or apoptosis in response to DNA damage or when exogenously expressed. However, how they trigger apoptosis remains unresolved. After stable transduction of either p73α or p73β, a greater apoptotic response was observed for p73β in both primary and tumor cells. Consistently, blocking ectopic and endogenous p73β expression by specific shRNA significantly decreased apoptotic levels after DNA damage. We found that p73β targets the apoptotic program at multiple levels: (i) facilitating caspase activation through p53-dependent signals and (ii) inducing p57^KIP2, while down-regulating c-IPA1 and IEX1 through a p53-independent mechanism. p73β-mediated apoptosis was considerably reduced after inhibition of p57^KIP2 by small interfering RNA, IEX-1 overexpression, and in mouse embryo fibroblasts derived from p57^−/− mice. Data from this study offer evidence for the apoptotic activity exclusive of p73β. In the clinical context, these results might have potential therapeutic implications, because p73β could induce alternative apoptotic responses in tumors harboring p53 mutations.