High levels of homocysteine, a non-protein-forming, sulfur-containing amino acid, have been associated with elevated cardiovascular risk in observational studies. Support for the homocysteine hypothesis comes from 2 primary lines of epidemiologic evidence, observational studies, such as case control and cohort studies, and studies of genetic variation. On the basis of unequivocally supportive epidemiologic data, a series of large randomized controlled trials of homocysteine lowering through folic acid supplementation were launched. The recently reported results of the 3 large, randomized clinical trials (SEARCH, WENBIT, WAFACS) in combination with those previously reported (CHAOS-2, VISP, NORVIT, HOPE-2) effectively rule out the possibility of large effect on risk of coronary heart disease, stroke, and all-cause mortality. Although the potential for prevention of atherosclerotic cardiovascular disease in adults through folic acid supplementation has not yet been substantiated, folic acid supplementation prenatally may reduce congenital heart defects in offspring.