Homocysteine has been identified as an independent risk factor for atherosclerotic and thrombotic disease. Both arterial (cerebrovascular, carotid, coronary, and peripheral arterial) and veno-occlusive disease, jointly termed vascular occlusive disease (VOD) in this review, have been associated with hyperhomocysteinemia. In cases of homocystinuria, plasma homocysteine levels are markedly elevated. In this setting, the association between homocysteine and VOD seems clear. However, in cases of mild to moderate homocysteinemia, controversy remains regarding the association between homocysteine and VOD. In part this controversy occurs because VOD has multiple etiologies. Similarly, homocysteine levels are affected by several factors including vitamin status, age and gender, and genotype of the patient. The multiple etiologies of both VOD and hyperhomocysteinemia make controlled studies assessing their interrelationship difficult to perform. This review will attempt to present studies that either support or rebut homocysteine as an independent risk factor for vascular occlusive disease and will show that the study of homocysteine and thrombosis remains an active area of research.