Homocysteine (Hcy) arises as an intermediate in methionine metabolism. It is produced as a result of S-adenosylmethionine-dependent transmethylation reactions and is removed, either by remethylation (conversion to methionine) or transsulfuration (conversion to cysteine). These pathways are highly dependent on B-vitamin status and, consequently, Hcy levels are very sensitive to B-vitamin deficiency, particularly that of folate, B12 and pyridoxal. Elevated plasma Hcy is an independent risk factor for a number of chronic diseases, such as cardiovascular disease, Alzheimer’s disease and osteoporosis. Elevated Hcy is associated with a higher risk of cardiovascular disease in diabetes mellitus than in the general population. Diabetes affects plasma Hcy in two quite different ways. In newly diagnosed Type 1 diabetes, plasma Hcy is often decreased whereas when diabetes is advanced, particularly when renal complications develop, plasma Hcy becomes elevated. Plasma Hcy is inversely related to glomerular filtration rate, regardless of the presence of diabetes. We have examined these phenomena in rats. We find that plasma Hcy is lower in rat models of both Type 1 (streptozotocin-induced) and Type 2 (ZDF fa/fa) diabetes. This decrease is accompanied by increased hepatic activities of two enzymes that remove Hcy, cystathionine beta-synthase and betaine:homocysteine methyltransferase. We have also found, in rat H4IIE cells, that insulin directly decreases the expression of these genes. Two consequences of the increased betaine:homocysteine methyltransferase activity in the diabetic rats are substantially reduced liver betaine levels and an enhanced ability of betaine to decrease Hcy production by isloated hepatocytes. Studies in rats have also revealed a major role for the kidney in the metabolism of plasma Hcy; we find a substantial arterial-renal venous difference for Hcy across the rat kidney. Since urinary Hcy is trivial, this implies a substantial intra-renal metabolism of Hcy. This occurs, via the transsulfuration pathway, in the cells of the proximal tubules. These observations are consistent with the increased Hcy that occurs in renal disease although data on renal Hcy metabolism in humans remain controversial.