Currently used antithrombotics such as heparin have a number of potential limitations that may be overcome by the new class of agents that directly inhibit thrombin. These agents variously block the active catalytic and/or the anion binding exosites of the thrombin molecule and are potent and specific inhibitors of thrombin's many biological actions, as demonstrated by in vitro and animal models of thrombosis. Preliminary data indicate that the direct antithrombins are safe and efficacious in humans, and their use in acute coronary syndromes and coronary angioplasty in place of heparin has yielded promising early results. Phase III trials in these clinical settings are currently under way. Newer antithrombotics that inhibit thrombin generation and thrombin activity at various strategic points within the coagulation cascade are also in the early stages of development.