The inability of the heparin-antithrombin complex to inhibit fibrin-bound thrombin limits the utility of heparin for treatment of arterial thrombosis. In contrast with heparin, melagatran, a direct thrombin inhibitor (DTI), is equally effective at inhibiting fluid-phase thrombin and thrombin bound to fibrin. This reflects the ability of melagatran, a reversible, active site-directed DTI, to access the active site of thrombin even when it is fibrin-bound. Because bivalent DTIs, such as hirudin, compete with fibrin for access to the fibrin-binding site on thrombin, bivalent DTIs produce less inhibition of fibrin-bound thrombin than free thrombin when given in low doses. Consequently, higher doses of hirudin are needed for complete inhibition of fibrin-bound thrombin resulting in a steep dose-response curve. This phenomenon, combined with the fact that hirudin irreversibly inhibits thrombin, may account for hirudin's narrow therapeutic window. In a rabbit arterial thrombosis prevention and ear bleeding model, melagatran produced less bleeding than hirudin when the two agents were given at doses that produced nearly complete inhibition of thrombosis. The more favourable benefit-to-risk profile of melagatran in this model likely reflects better access to fibrin-bound thrombin and the reversible nature of the melagatran/thrombin complex. The theoretical advantages of melagatran may endow it with mechanistic advantages over heparin, and safety advantages over hirudin. Large-scale clinical trials are under way to evaluate the utility of an orally active prodrug form of melagatran for prevention and treatment of venous and arterial thrombosis.