Oxygen is essential for most life forms, but it is also inherently toxic due to its biotransformation into reactive oxygen species (ROS). In fact, the development of many animal and plant pathological conditions, as well as natural aging, is associated with excessive ROS production and/or decreased antioxidant capacity. However, a number of animal species are able to tolerate, under natural conditions, situations posing a large potential for oxidative stress. Situations range from anoxia in fish, frogs and turtles, to severe hypoxia in organs of freeze-tolerant snakes, frogs and insect larvae, or diving seals and turtles, and mild hypoxia in organs of dehydrated frogs and toads or estivating snails. All situations are reminiscent of ischemia/reperfusion events that are highly damaging to most mammals and birds. This article reviews the responses of anoxia/hypoxia-tolerant animals when subjected to environmental and metabolic stresses leading to oxygen limitation. Abrupt changes in metabolic rate in ground squirrels arousing from hibernation, as well as snails arousing from estivation, may also set up a condition of increased ROS formation. Comparing the responses from these diverse animals, certain patterns emerge. The most commonly observed response is an enhancement of the antioxidant defense. The increase in the baseline activity of key antioxidant enzymes, as well as 'secondary' enzymatic defenses, and/or glutathione levels in preparation for a putative oxidative stressful situation arising from tissue reoxygenation seem to be the preferred evolutionary adaptation. Increasing the overall antioxidant capacity during anoxia/hypoxia is of relevance for species such as garter snakes (Thamnophis sirtalis parietalis) and wood fogs (Rana sylvatica), while diving freshwater turtles (Trachemys scripta elegans) appear to rely mainly upon high constitutive activities of antioxidant enzymes to deal with oxidative stress arising during tissue reoxygenation. The possibility that some animal species might control post-anoxic ROS generation cannot be excluded.