Chronic lower extremity wounds include ulceration of the leg and foot. The underlying pathology that causes these conditions includes venous insufficiency, arterial disease, diabetes, and other less common disorders. Since the introduction of the homocysteine theory more than 30 years ago, considerable evidence has demonstrated hyperhomocysteinemia to be an independent risk factor for venous and arterial thrombosis, atherosclerosis and cardiovascular disease. Although any cause-effect relationship remains to be determined, hyperhomocysteinemia as a risk factor for these events suggests that elevated levels of homocysteine may also be a marker of chronic lower limb ulceration. This review addresses the metabolism of homocysteine, mechanisms of vascular injury, a role for hyperhomocysteinemia in lower extremity wounds and possible means of treatment.