Obesity and type 2 diabetes mellitus have reached epidemic proportions in the US, and indeed, globally. While microvascular complications contribute to considerable morbidity, much of the excess mortality (around 70%) is due to macrovascular disease. Hyperglycemia has predictable toxic effects on multiple organs (‘glucotoxicity’) including the pancreas, where it impairs insulin secretion and insulin gene expression through mechanisms that lead to glucose densensitization and β-cell exhaustion, eventually resulting in irreversible β-cell failure. There is robust evidence to suggest that strict glycemic control reduces diabetic microvascular complications (retinopathy, nephropathy, and neuropathy) in both primary- and secondary-prevention settings. While unequivocal evidence that intensive glycemic control reduces the risk of death due to macrovascular disease is lacking, meta-analytic data and controlled clinical trial data suggest there may still be clinically significant lowering of the risk for macrovascular endpoints through strict glycemic control. Cardiovascular disease in a diabetic patient is a collusion of several factors besides hyperglycemia, such as hypertension, dyslipidemia, diffuse endothelial dysfunction, hypercoagulability, and inflammation. It is important to address lifestyle issues such as maintenance of ideal bodyweight, good dietary practice, smoking cessation, and regular exercise in the comprehensive risk management of a diabetic patient, in order to reduce the vascular complications. Large, ongoing clinical trials such as ACCORD (Action to Control Cardiovascular Risk in Diabetes) are likely to establish the potential benefits of glycemic control in preventing or postponing macrovascular complications of diabetes.