Peripheral artery disease (PAD) affects more than 200 million adults worldwide. Patients with lower extremity PAD have a heightened risk for cardiovascular events because of the systemic nature of atherosclerosis, and benefit from treatment with risk factor-modifying therapies. Limb symptoms in PAD include intermittent claudication and diminished walking ability. Arterial obstruction from atherosclerotic lesions initiates limb ischemia; however, decreased perfusion incompletely determines the clinical expression of PAD and its response to therapy. Potential mechanistic drivers of claudication in addition to arterial obstruction include inflammation, vascular dysfunction, reduced microvascular flow, impaired angiogenesis, and altered skeletal muscle function. An improved understanding of the pathophysiology of limb symptoms has the potential to accelerate development of novel therapeutic strategies to increase functional capacity in patients with PAD.