Oxidative stress, which is caused by endogenous and exogenous reactive-oxygen-species (ROS) formation, may significantly affect health-span and longevity. Endogenous oxidative stress could be attenuated in two ways: by the reduction of ROS formation and by quenching ROS with antioxidants. Numerous results of clinical trials in which individuals received one or more synthetic antioxidants failed to demonstrate conclusive benefits of antioxidant supplementation. Even oral supplementation with endogenous antioxidant enzymes cannot alter the antioxidant balance due to their degradation in the digestive system. Likewise, life-span or health-span is not increased significantly in genetically modified models overexpressing antioxidant enzymes. An alternative approach to attenuate the ROS-induced stress/damage may be through triggering an adaptive stress response in order to increase the endogenous antioxidant and damage repair processes. Moderate stress induced by CR, physical activity or mimetic compounds may induce such activation of endogenous antioxidative defence and cellular repair processes. These processes may increase cellular resistance to subsequent more severe stress and do not seem to interfere with ROS-dependent cellular signalling.