The combination of pioglitazone hydrochloride, a thiazolidinedione, and glimepiride, a sulfonylurea, has been approved in many countries worldwide as an oral agent for the management of type 2 diabetes. Glimepiride stimulates insulin secretion from the pancreas with a decreased risk of hypoglycemia compared to glyburide. Pioglitazone increases glucose uptake in the periphery while decreasing glucose production by the liver. Combined, the two agents increase the body's sensitivity to insulin to reduce hemoglobin A1c levels by 1-2%. Pioglitazone and glimepiride also produce favorable effects on lipid profiles and blood pressure. Additionally, pioglitazone has proven to decrease the risk of certain cardiovascular events, providing evidence for macrovascular benefits. Side effects are minimal with pioglitazone and glimepiride, with weight gain and edema providing the most discomfort and complications. Patients must be monitored for the development of heart failure, though the risk is small. Guidelines are in place to limit patient selection for the use of pioglitazone based on cardiac risk factors. In general, pioglitazone and glimepiride are well tolerated.