Children with homocystinuria have markedly elevated plasma homocysteine concentrations and increased risks of stroke and coronary heart disease (CHD). Supplementation with folic acid, vitamin B6, and vitamin B12 lower homocysteine levels and such therapy is remarkably effective in delaying the occurrence of vascular events in affected individuals. The relevance, if any, of moderately elevated homocysteine levels to cardiovascular disease in the general population is uncertain. The results of retrospective studies of homocysteine and risk of cardiovascular disease (where blood is collected after the onset of disease) indicate that CHD or stroke patients invariably have higher homocysteine levels than age-matched controls. In contrast, the results of prospective studies (where blood is collected before onset of disease) show much weaker associations of homocysteine with cardiovascular disease. This article examines the background, epidemiological evidence relating homocysteine with vascular disease, and effects of vitamin supplements on homocysteine concentrations. Large-scale clinical trials of folic acid-based vitamin supplements are currently in progress to test whether lowering blood homocysteine levels can reduce the risks of CHD and stroke.