Peripheral arterial disease leads to lower extremity ischemia and limb loss, and is linked to cardiovascular events. The anatomical extent of lower extremity atherosclerosis fails to fully explain ischemic symptoms or predict the development of critical limb ischemia. Endothelial dysfunction is known to contributed to the pathogenesis and clinical expression of coronary artery disease, but the importance of endothelial dysfunction in peripheral arterial disease remains incompletely understood. Endothelial dysfunction could contribute to lower extremity ischemia by impairing blood flow responses to ischemia, collateral formation and arterial remodelling, and by promoting vasospasm, thrombosis, plaque rupture and lesion progression. There is a need for additional studies examining the contribution of endothelial dysfunction to the pathogenesis of peripheral arterial disease, and the potential role of endothelial dysfunction as a surrogate marker with utility in the management of patients.