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The thiazolidinediones (TZDs) rosiglitazone and pioglitazone are newer additions to the antidiabetic armamentarium and are indicated for the treatment of type 2 diabetes mellitus (T2DM) in the United States. The TZDs are peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists that provide clinically effective glycemic control and unique pharmacologic effects on multiple risk factors for T2DM-related morbidity, including improvement of insulin sensitivity and endothelial dysfunction, reduction of blood pressure, and amelioration of dyslipidemia. Weight gain and fluid retention occur with TZD therapy, especially when they are administered in higher doses and in combination with insulin. Although fluid retention associated with the use of TZDs is generally mild and reversible, these agents should not be used in patients with New York Heart Association Class III or IV heart failure symptoms. The findings of ongoing, long-term, prospective studies will clarify the role of the TZDs in the treatment of T2DM, particularly in terms of the durability of improvements in glycemic control, insulin sensitivity, pancreatic β- cell function, and cardiovascular health.