Hirudin, the first specific thrombin inhibitor, which was used clinically, stems from medicinal leeches and is produced today by recombinant technology. R-hirudins have been studied in many clinical trials. R-hirudin has been shown to be more effective than low molecular weight heparin in the prevention of deep venous thrombosis after total hip replacement. In acute coronary syndromes hirudin and the chimeric oligoaminoacid peptide bivalirudin have also been effective. In acute coronary syndromes and when administered together with aspirin high doses of hirudin were associated with an increased risk of bleeding. Hirudin and argatroban successfully prevented thrombotic episodes in patients with heparin-induced thrombocytopenia type II. Several new orally active specific thrombin inhibitors are in development. The combined use of subcutaneous and oral administration of ximelagatran in patients with hip or knee replacement has led to promising results. It seems likely that in the future oral thrombin inhibitors may replace vitamin K-antagonists in some indications. The pentasaccharide fondaparinux is an indirect inhibitor of F Xa. Its anticoagulant and antithrombotic effect depends on the activation of antithrombin. Fondaparinux has shown remarkable antithrombotic efficacy in patients with high risk orthopedic surgery and has been approved in the US and in Europe. Several new low molecular weight specific F Xa-inhibitors are in different stages of development for i.v. and oral use.