The mitochondrion plays a critical role in the development of Oxygen (O2)-related diseases. While research has predominantly focused on hypoxia-sensitive mammals as surrogates for humans, the use of animals which have naturally evolved anoxia tolerance has been largely ignored. Remarkably, some animals can live in the complete absence of O2 for days, months and even years, but surprisingly little is currently known about mitochondrial function in these species. In contrast to mammals, mitochondrial function in anoxia-tolerant animals is relatively insensitive to in vitro anoxia and reoxygenation, suggesting that anoxia tolerance transcends to the level of the mitochondria. Furthermore, long-term anoxia is associated with marked changes in the intrinsic properties of the mitochondria from these species, which may afford protection against anoxia-related damage. In the present review, we highlight some of the strategies anoxia-tolerant animals possess to preserve mitochondrial function in the absence of O2. Specifically, we review mitochondrial Ca(2+) regulation, proton leak, redox signaling and mitochondrial permeability transition, in phylogenetically diverse groups of anoxia-tolerant animals. From the strategies they employ, these species emerge as model organisms to illuminate novel interventions to mitigate O2-related mitochondrial dysfunction in humans.