Type 2 diabetes has now reached epidemic proportions across the world and is the cause of substantial morbidity and mortality. It is now well established that intensive control of blood glucose can significantly reduce and ameliorate the microvascular complications of retinopathy, nephropathy, and neuropathy. Unfortunately however, nearly 80% of type 2 diabetic patients die from macrovascular cardiovascular disease. This increased incidence of atherosclerotic disease is intricately associated with insulin resistance, which is a major pathophysiologic abnormality in type 2 diabetes. There is strong evidence that insulin resistance is intricately involved in the development of not only hyperglycemia, but also dyslipidemia, hypertension, hypercoagulation, vasculopathy, and ultimately atherosclerotic cardiovascular disease. This cluster of metabolic abnormalities has been termed the “insulin resistance or metabolic syndrome.” The thiazolidinediones (rosiglitazone and pioglitazone) constitute a new class of oral antidiabetic agents which are “insulin sensitizers” and exert direct effects on the mechanisms of insulin resistance. Through their PPAR-γ agonist effects, the thiazolidinediones not only improve insulin sensitivity and glycemic control with reduced insulin requirements, but also have potentially favorable effects on other components of the metabolic syndrome. These beneficial effects on lipid metabolism, vascular tone, and endothelial function might directly and indirectly influence cardiovascular risk by favorably altering several proatherogenic metabolic processes. Long-term studies are needed to determine whether the insulin-sensitizing effects of the thiazolidinediones have the potential to prevent or delay the development of type 2 diabetes as well as premature atherosclerotic cardiovascular disease, morbidity, and death.