Thrombin inhibitors play an important role as part of current (and potential future) thrombolytic-antithrombotic regimens for acute myocardial infarction. Heparin has been shown to improve infarct-related artery patency following TPA and is an integral adjunct to front-loaded TPA and aspirin, the regimen that has been demonstrated to be superior to standard thrombolytic regimens. The initial experience with direct thrombin inhibitors as an adjunct to thrombolytic therapy has shown promising results. They provide a predictable, dose-dependent increase in aPTT with a more stable level of anticoagulation than does heparin. Indices of infarct-related artery patency have been improved by direct thrombin inhibitors, and reocclusion appears to be reduced. In parallel with this improvement in coronary reperfusion, there are promising trends toward a lower incidence of clinical events as compared with heparin. Thus, it is hoped that these favorable initial results can be confirmed in the larger phase III trials and that the direct thrombin inhibitors will further improve the outcome of patients with acute myocardial infarction.