Beyond glycemic control, the thiazolidinediones (TZDs) provide numerous cardiovascular benefits. Clinical data support a role for the TZDs in lowering blood pressure, correcting dyslipidemia, improving vascular structure and function, decreasing inflammation, improving the adipokine profile, reducing systemic oxidative stress, and possibly in stabilizing coronary plaques that may be prone to rupture. Data from the first outcomes trial assessing a TZD in reducing cardiovascular morbidity and mortality have recently been reported. Results were promising, but not conclusive. Therefore, other large studies currently underway should provide greater insight into the role of the TZDs in modifying cardiovascular risk in patients with type 2 diabetes. Reported side effects of the TZDs include fluid retention, worsening of heart failure, and weight gain. Recent research is beginning to clarify the mechanisms associated with these potential side effects and may result in the expanded use of this drug class in patients with heart failure. Because of the unique mechanism of action of this drug class that addresses a fundamental pathophysiolgical phenomenon in type 2 diabetes, namely, improving insulin resistance, and the growing body of evidence supporting cardiovascular benefits, strong consideration should be given to utilizing the TZDs early in the clinical course of diabetes.