Numerous retrospective and prospective observational studies support an association between elevated homocysteine and increased risk for myocardial infarction, stroke, and peripheral vascular disease. Although folic acid therapy substantially reduces homocysteine levels, recent large, randomized controlled trials failed to translate folic acid-induced homocysteine reduction into clinical benefit for the secondary prevention of cardiovascular events. These studies are compelling and have generated some newfound skepticism regarding a clinical role for folic acid therapy. Because these intervention trials have been limited to patients with mild hyperhomocysteinemia, the results of the trials imply that folic acid therapy may be best suited for individuals with more robustly elevated homocysteine levels. Furthermore, the potential benefit of folic acid therapy for primary prevention in individuals at low- or intermediate-risk for atherothrombotic disease has not been studied to date. Thus, at this time, folic acid therapy for borderline or mild hyperhomocysteinemia is not recommended. However, the role of folic acid therapy in patients with intermediate or severe hyperhomocysteinemia, or for primary prevention of cardiovascular diseases, remains unresolved.