For most animals, oxygen is essential for the continual function of cellular processes. The absence of oxygen, termed anoxia, is associated with a number of pathological states such as ischemia, stroke, angina and cancer. Remarkably, certain vertebrates have evolved to live without oxygen for days, weeks and even months. Anoxia tolerance in these animals is derived from a wide array of physiological adaptations. As the study of ectothermic physiology advances, the cellular mechanisms underlying these adaptations are becoming resolved. Mitochondrial function is of particular interest, as it is the final arbitrator of life and death during oxidative stress. In particular, regulation of the F1F0 ATPase (Complex V of the electron transport chain) is emerging as a fundamental component of mitochondrial and cellular anoxia survival across vertebrates. A reduction in Complex V activity serves to preserve precious ATP supplies during acute anoxia and may protect against reactive oxygen species generation. Recent data suggests a downregulation of Complex V is also characteristic of long term anoxic survival. Importantly, this anoxic survival strategy has been identified in all classes of vertebrates, which suggests fundamental mechanisms have been conserved throughout the animal kingdom to endure periods without oxygen.