The postulate that thrombotic coronary occlusion was the underlying pathophysiologic event in the acute coronary ischemic syndromes was developed over the years 1912-60. This concept prompted the development of anticoagulant and thrombolytic therapies and the use of acetylsalicylic acid in such patients. A central role for coronary thrombus came to be questioned in the 1970s and the use of anticoagulants dramatically decreased and thrombolytic therapy was little used. Coronary angiographic studies among patients during the early hours of evolving myocardial infarction re-established the etiologic role of coronary thrombosis in the acute coronary ischemic syndromes, and were supplemented by careful autopsy studies. The concepts of meta-analysis lead to more accurate interpretations of earlier randomized, controlled trials of anticoagulant, antiplatelet and thrombolytic therapies. Large clinical trials have provided confirmatory evidence and have established the benefits of antiplatelet and thrombolytic agents in the acute ischemic syndromes. The benefit of long term anticoagulation following myocardial infarction has been demonstrated, although the benefit during the acute in-hospital phase of myocardial infarction is still uncertain. Currently, clinical trials are evaluating new antithrombins, antiplatelet agents, and thrombolytic agents and regimens among patients with unstable angina, acute myocardial infarction, and undergoing angioplasty for complex coronary lesions.