It is not understood why healthy tissues can exhibit varying levels of sensitivity to the same toxic stimuli. Using BH3 profiling, we find that mitochondria of many adult somatic tissues, including brain, heart, and kidneys, are profoundly refractory to pro-apoptotic signaling, leading to cellular resistance to cytotoxic chemotherapies and ionizing radiation. In contrast, mitochondria from these tissues in young mice and humans are primed for apoptosis, predisposing them to undergo cell death in response to genotoxic damage. While expression of the apoptotic protein machinery is nearly absent by adulthood, in young tissues its expression is driven by c-Myc, linking developmental growth to cell death. These differences may explain why pediatric cancer patients have a higher risk of developing treatment-associated toxicities. Display omitted •Cells within healthy adult brain, heart, and kidneys are apoptosis refractory•Early in life, brain, heart, and kidney cells are primed for apoptosis•Dynamic regulation of apoptosis affects cell fate in response to genotoxic damage•The apoptosis pathway is modulated by c-Myc, linking cellular growth with death To explain how pediatric, compared with adult, cancer patients have a higher risk for treatment-associated toxicities, Sarosiek et al. find that many tissues in children and young mice are primed for apoptosis, whereas adult tissues are not due to differences in the expression of apoptotic proteins.