Thrombin is a pivotal molecule in acute myocardial infarction (MI) because of its extensive procoagulant and prothrombotic actions. Antithrombin therapy is an important component of the pharmacotherapy for acute MI. The standard agent used in clinical practice, unfractionated heparin (UFH), is associated with the disadvantages of variable anticoagulant effect, inability to inhibit clot-bound thrombin, neutralization by platelet factor 4, and the propensity to cause thrombocytopenic complications. Novel thrombin inhibitors have been developed to overcome these disadvantages. Although possessing the property of inhibiting both fluid-phase and clot-bound thrombin, the direct thrombin inhibitor hirudin has been shown to give marginal benefits over UFH as adjunct to fibrinolysis in ST-elevation MI. Bivalirudin, another direct thrombin inhibitor, is able to reduce reinfarction in patients treated with streptokinase and is a new anticoagulant treatment option in this setting. The pharmacokinetic characteristics of better availability, longer half-life, and dose-independent clearance together with the ability of inhibiting both thrombin generation and activity make the low-molecular-weight heparins (LMWHs) an attractive altative to UFH. The favorable benefit/risk profile of the LMWHs as adjunct to different generations of fibrinolytic agents is setting the stage for larger clinical trials to confirm their role as the antithrombin agent of choice for STEMI.