Thrombin mediates acute vascular thrombosis following mechanical denuding injury or spontaneous rupture of atherosclerotic plaques. In the process of generating thrombin, factor VII/VIIa binds avidly with tissue factor exposed on cellular membranes, leading to sequential activation of coagulation serine proteases via macromolecular catalytic complexes on phospholipid surfaces. At sites of disrupted arteries thrombin activates platelets, blood leukocytes, endothelium, and vascular SMCs by cleaving G protein-coupled TRs, mediating SMC intimal proliferation in the formation of neointimal vascular lesions. Therapeutic strategies targeting thrombin include inactivation of bound thrombin, inhibition of TR activation by thrombin, and interruption of thrombin production. In patients having orthopedic surgery, inactivating bound thrombin with direct antithrombins markedly reduces venous thromboembolism as compared with heparin or its derivatives, without significant impairment of hemostasis. Antithrombotic effects in arterial thromboembolism, such as acute coronary syndrome, are not conclusively benefitted by systemic direct antithrombins when administered at safe levels, because interrupting TR-dependent platelet thrombosis demands systemic levels of direct antithrombins that compromise hemostatic function. Alternative safer strategies evolving from preclinical studies include (1) inhibiting thrombin activation of TRs, thereby abolishing platelet recruitment in arterial thrombogenesis, while sparing fibrin formation in hemostatic plugs; (2) enhancing the formation of endogenous activated protein C by protein C-selective thrombin mutants; and (3) preventing thrombin production by inhibiting precursor serine protease function and interrupting the formation of both acute thrombosis and vascular lesion formation. Tissue factor pathway antagonists are particularly promising because they exhibit both efficacy and safety in the prevention of thrombosis and vascular lesions.