Homocysteine is a sulfur-containing aminoacid produced during metabolism of methionine. Since 1969 the relationship between altered homocysteine metabolism and both coronary and peripheral atherotrombosis has been known; in recent years experimental evidences have shown that elevated plasma levels of homocysteine are associated with an increased risk of atherosclerosis and cardiovascular ischemic events. Several mechanisms by which elevated homocysteine impairs vascular function have been proposed, including impairment of endothelial function, production of Reactive Oxygen Species (ROS) and consequent oxidation of low-density lipids. Folic acid and B vitamins, required for remethylation of homocysteine to methionine, are the most important dietary determinants of homocysteinemia and daily supplementation typically lowers plasma homocysteine levels. Recently, large-scale intervention trials have been conducted to determine whether lowering homocysteine concentrations through B vitamins supplementation can decrease cardiovascular risk in healthy subjects or improve survival in patients with coronary heart disease. Some of these trials found no significant beneficial effects of combined treatment with folate and vitamin B12, with or without vitamin B6, in spite of adequate homocysteine lowering. In conclusion, it is still unclear whether decreasing plasma levels of homocysteine through diet or drugs may be paralleled by a reduction in cardiovascular risk.