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.