Age-associated rises in oxidative damage are assumed to be a central phenomenon of aging. Their attenuation is an aim for both healthy aging and life extension. This review intends to critically discuss the potential of anti-oxidant actions, but even more to direct the attention to the modes of radical avoidance and to regulatory networks involved. Mitochondria seem to play a decisive role in radical formation and cellular decline. Avoidance and repair of disruptions in the electron transport chain reduce electron leakage and, thus, oxidative damage. Several low molecular weight compounds, such as melatonin, its metabolite N¹-acetyl-5-methoxykynuramine, resveratrol, α-lipoic acid, and various mitochondrially targeted nitrones are capable of supporting mitochondrial electron flux. Some of them have been successfully used for extending the lifespan of experimental animals. Importantly, chemopreventive effects of these substances against cancer development should not be confused with a slowing of the aging process. We also focus on connections between these compounds and mitochondrial biogenesis, including the roles of sirtuins and signaling via peroxisome proliferator-activated receptor-γ coactivator-1α, the participation of the circadian oscillator system in radical avoidance, as well as the potentially beneficial or detrimental effects of NO, as either a regulator or a source of mitochondrial dysfunction. Especially in the central nervous system, anti-excitatory actions by melatonin, kynurenic acid and theanine are discussed, which seem to prevent calcium overload that results in mitochondrial dysfunction. New findings on direct binding of melatonin to the amphipathic ramp of Complex I may indicate an additional regulatory role in the avoidance of electron leakage.