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Plasminogen activator inhibitor‐1 (PAI‐1) is the major physiologic inhibitor of tissue‐type plasminogen activator in plasma, and is elevated in a variety of clinical situations that are associated with increased risk of ischemic cardiovascular events. Recent insights into the biology of PAI‐1 suggest that it is more than just an innocent bystander in the pathogenesis of ischemic heart disease. Elevated PAI‐1 levels appear to increase the risk of atherothrombotic events and may also promote the progression of vascular disease. The development and testing of specific PAI‐1 antagonists will enable basic and clinical investigators the opportunity to test the hypothesis that vascular PAI‐1 excess promotes the development of intravascular thrombosis and atherosclerosis.