Patients with type 2 diabetes mellitus are at increased risk for macrovascular disease complications. Hyperglycemia and atherosclerotic disease clearly are associated, and biologic intermediates mediated by hyperglycemia exist. Our understanding of the pathobiology linking hyperglycemia and atherosclerotic disease continues to evolve. Modulation of the advanced glycation end product (AGE) receptor for AGE (RAGE)/soluble RAGE (sRAGE) system, the thromboxane receptor, and C-peptide comprise just a few of the plausible links between dysglycemia and atherosclerosis. It seems intuitive, therefore, that therapeutic management of blood glucose in patients with diabetes should reduce macrovascular disease and related deaths. However, studies of glucose-lowering therapies performed to date yield qualitatively and quantitatively different results. No definitive proof of the concept is yet available, although it remains probable, with investigations presently under way. Numerous interventions extending beyond glucose control, including lifestyle modification, pharmacologic therapy with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), aspirin, and angiotensin-converting enzyme inhibitors, as well as aggressive blood pressure control independent of blood pressure levels, have proved to be of cardiovascular benefit in the high-risk population of patients with diabetes. Thus, all of these interventions should be used in addition to glucose management in all patients with diabetes who are at increased risk for cardiovascular disease.