Cardiovascular disease disproportionately affects people with diabetes and is a leading cause of death. Glycemic control has so far not been conclusively shown to decrease cardiovascular events. The therapeutic agents used in treating glycemia have different effects on cardiovascular risks and, therefore, may have different effects on outcome. Insulin sensitizers impact cardiovascular risk factors, including dyslipidemia and fibrinolysis. Metformin is the only oral antidiabetic medication shown to decrease cardiovascular events independent of glycemic control. Thiazolidinediones improve insulin resistance and lower insulin concentrations, which is beneficial because hyperinsulinemia is an independent predictor of cardiovascular disease. Insulin therapy acutely reduces cardiovascular mortality and morbidity in patients with diabetes and known coronary artery disease and also in patients with hyperglycemia when critically ill, but the long-term effects are unclear. In contrast, insulin secretagogues have very little effect on both cardiovascular risk factors and outcomes.