Traditional anticoagulant drugs, including unfractionated heparin and warfarin, have several limitations. A new strategy for the design of new antithrombotic drugs is based on selective inhibition of a specific coagulation factor. These include direct thrombin inhibitors and factor Xa inhibitors. Two parenteral direct thrombin inhibitors, lepirudin and argatroban, have FDA approval for the management of heparin-induced thrombocytopenia. Ximelagatran, an oral prodrug of the direct thrombin inhibitor melagatran, has shown efficacy in the prevention and treatment of venous thromboembolism as well as stroke prevention in patients with atrial fibrillation. Fondaparinux is a synthetic pentasaccharide, which binds to antithrombin, thereby indirectly selectively inhibiting factor Xa. Fondaparinux has demonstrated its efficacy compared to low-molecular-weight heparin in randomized clinical trials and is FDA approved for the prevention and treatment of venous thromboembolism. A number of oral direct factor Xa inhibitors as well as other oral direct thrombin inhibitors are in clinical development for the prevention and treatment of thrombosis.