Coronary artery thrombosis superimposed on a disrupted atherosclerotic plaque has emerged as the pivotal pathophysiologic event in acute coronary syndromes (i.e., unstable angina, myocardial infarction, and sudden death). The various clinical manifestations depend on the extent and duration of thrombus deposition, which are determined by several local and systemic thrombogenic risk factors. The thrombotic response to plaque disruption involves both platelet activation and thrombin generation. Accordingly, combined treatment with aspirin and heparin has proved more efficacious than either treatment alone in the risk reduction of serious cardiac events in patients with unstable angina or non-Q-wave infarction. However, withdrawal of heparin is, even after prolonged treatment, associated with an increased short-term risk of serious cardiac events relative to the risk in patients given only aspirin. Furthermore, the long-term relative event rate seems not to be influenced by administration of heparin or direct antithrombins in the acute phase. Both transient hypercoagulability associated with heparin withdrawal and continuous thrombin generation over a longer term related to the underlying disease may explain the rebound in clinical events. Longer duration of combined antiplatelet and anticoagulant treatments, e.g., until healing of the culprit lesion or even until stabilization of vulnerable, yet nondisrupted plaques, may improve long-term clinical outcome.