Cardiovascular events in patients with type 2 diabetes mellitus are a major problem in clinical practice, and patients with diabetes have derived less benefit from advances in preventive and interventional cardiology. Tighter goals for metabolic management and attention to nontraditional risk factors may be needed in this patient group. Insulin resistance rather than hyperinsulinemia is thought to underlie cardiovascular disease in patients with diabetes. Insulin resistance is associated with cardiovascular events and a wide range of traditional and nontraditional risk factors for cardiovascular disease (e.g., endothelial dysfunction, dyslipidemia, inflammation, vascular wall abnormalities). Therapy with lifestyle modifications, metformin, or thiazolidinediones (TZDs) corrects many of the abnormalities associated with diabetes in addition to lowering blood glucose and correcting diabetic dyslipidemia. TZDs, acting via the peroxisome proliferator-activated receptor–γ, affect a number of mediators involved in the development of the cardiovascular complications of diabetes, including lipid profiles, vascular changes, and inflammatory mediators. TZDs decrease plasminogen activator–1 and C-reactive protein levels. They also reduce the extent of thickening of the carotid artery and reduce hyperplasia after coronary stent implantation. Insulin-sensitizing therapy with TZDs is a promising intervention for patients with diabetes at risk for adverse cardiovascular outcomes.