Homocysteine is a metabolic intermediate in methyl group metabolism that is dependent on a number of nutritional B-vitamin cofactors. An emerging aspect of homocysteine metabolism is its relation to health and disease. Perturbations of homocysteine metabolism, particularly intracellular and subsequently circulating accumulation of homocysteine (i.e., hyperhomocysteinemia), are associated with vascular disease risk, as well as other pathologies. However, intervention with B-vitamin supplementation has been shown to successfully restore normal homocysteine concentrations, but without concomitant reductions in disease risk. Thus, the mechanistic relation between homocysteine balance and disease states, as well as the value of homocysteine management, remains an area of intense investigation.