Morbidity and mortality are increased in diabetic patients with ischemic heart disease. Sulfonylureas are the therapeutic group most frequently used and contributing to this. Patients usually treated with sulfonylureas have increased cardiovascular mortality. This is probably attributed to the action of these drugs on the ATP-sensitive potassium channels via blocking the ischemic preconditioning. This article puts forward evidence on sulfonylureas cellular and molecular pharmacodynamics and the real clinical incidence in the ATP-sensitive potassium channels inhibition in the diabetic patient's ischemic heart.