Thiazolidinediones (TZDs) are insulin-sensitizing antidiabetes agents that act through the peroxisome proliferator-activated receptor-γ to cause a durable improvement in glycemic control in patients with type 2 diabetes mellitus. Although less well recognized, TZDs also exert a protective effect on β-cell function. In addition to their beneficial effects on glucose homeostasis, TZDs-especially pioglitazone-exert a number of other pleiotropic effects that make them ideal agents as monotherapy or in combination with other oral agents, glucagon-like peptide-1 analogs, or insulin. Pioglitazone improves endothelial dysfunction, reduces blood pressure, corrects diabetic dyslipidemia, and reduces circulating levels of inflammatory cytokines and prothrombotic factors. Pioglitazone also redistributes fat and toxic lipid metabolites in muscle, liver, β cells, and arteries, and deposits the fat in subcutaneous adipocytes where it cannot exert its lipotoxic effects. Consistent with these antiatherogenic effects, pioglitazone reduced major adverse cardiac event endpoints (ie, mortality, myocardial infarction, and stroke) in the Prospective Pioglitazone Clinical Trial in Macrovascular Events and in a meta-analysis of all other published pioglitazone trials. Pioglitazone also mobilizes fat out of the liver, improving liver function and histologic abnormalities in patients with nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Pioglitazone also reduces proteinuria, all-cause mortality, and cardiovascular events in patients with type 2 diabetes mellitus with a reduced glomerular filtration rate. These benefits must be weighed against the side effects of the drug, including weight gain, fluid retention, atypical fractures, and, possibly, bladder cancer. When low doses of pioglitazone are used (eg, 7.5-30 mg/d) with gradual titration, and physician recognition of the potential side effects are applied, the risk-to-benefit ratio is very favorable. Despite having similar effects on glycemic control, pioglitazone and rosiglitazone appear to have different effects on cardiovascular outcomes. Rosiglitazone has been associated with an increased risk of myocardial infarction, and its use in the United States is restricted because of cardiovascular safety concerns.