Control of intracellular redox balance has emerged as a primary function of the p53 network, with crucial implications for tumor suppression, aging, and cell metabolism. Mitochondria are central to redox homeostasis, produce energy, and trigger apoptosis and senescence: not surprisingly, many “old” and “new” functions of p53 appear to be based in mitochondria. Genetic and biomolecular evidence indicates that generation of reactive oxygen species (ROS) in mitochondria can be a deliberate and finely regulated cell response on which signaling by environmental stressors, oncogenes, and nutrients converge. p53 orchestrates mitochondrial redox signaling by the coordinated control of at least two key effectors: the superoxide scavenger MnSOD, and the ROS generator p66shc. This review presents recent evidence and emerging questions regarding the p53–MnSOD–p66shc connection, and discusses how dissection of a circuitry comprising a tumor suppressor, an antioxidant, and a molecule regulating cell survival and mammalian lifespan can provide a framework to address important aspects related to the intricate connection between metabolism, aging, and cancer. Antioxid. Redox Signal. 15, 1715–1727.