The signs and symptoms of peripheral arterial occlusive disease (PAD), including claudication, rest pain, and tissue loss, are consequences of compromised bioenergetics and oxidative tissue injury within the affected lower extremities. Compromised bioenergetics is the result of a combination of low blood flow through diseased arteries and diminished adenosine triphosphate production by dysfunctional mitochondria. The tissue injury appears to be secondary to increased production of reactive oxygen species by dysfunctional mitochondria and by inflammation, in association with ischemia and ischemia/reperfusion. In this review, we present the current histomorphologic, physiologic, and biochemical evidence defining the nature of this mitochondriopathy and discuss its contribution to the pathogenesis and clinical manifestations of PAD.