New anticoagulants have been designed using advances in the biotechnology and the biochemistry of the clotting factors. They are classified according to their target or their mechanism of action (AT-dependent or AT-independent). Antithrombotic activity after oral administration is another important property. This abstract is restricted to the synthetic pentasaccharide and the ximelagatran/melagatran. Fondaparinux (Arixtra) is a chemically synthesized methoxy derivative of the natural pentasaccharide (MW=1728 Da). Fondaparinux has nearly complete bioavailabity after subcutaneous injection. The elimination half-life is about 17 hours. Fondaparinux is cleared from the kidneys. In contrast to heparin, fondaparinux does not interact with plasma proteins other than antithrombin and it does not cross-react in vitro with heparin induced thrombocytopenia antibodies. Fondaparinux inhibits specifically FXa, although some other targets are suspected (FIXa and FVIIa). Endogenous levels of AT are the rate limiting factor for its anti-Xa activity. Fondaparinux, in contrast to direct FXa inhibitors (i.e. DX-9065a) inhibits free FXa but not the FXa bound to prothrombinase, and it does not prolong PT and aPTT. Fondaparinux inhibits thrombin generation in human plasma. We have shown that the inhibition of thrombin generation by fondaparinux is inversely correlated with thromboplastin concentration. This original observation may explain the absence of any effect of fondaparinux on PT. Melagatran dipeptide (MW=430 Da) is a specific, reversible direct thrombin inhibitor. It inhibits free and clot bound thrombin. Its half-life is 1.7-2.5 hours after i.v. or s.c. administration. Ximelagatran (Exantas), is a pro-drug with a hydroxyamidino instead of amidino-group and an esterified carboxyl-group. It is the first clinically used direct orally acting thrombin inhibitor. Ximelagatran after intestinal absorption is metabolized to melagatran. Melagatran is not metabolized and is cleared through the kidney. Among the specific FXa inhibitors the synthetic pentasaccharide (Fondaparinux-Arixtra) has been approved by FDA and several European health organizations for the prophylaxis of VTE in major orthopedic surgery. No specific antidote has been described for the new antithrombotics. Encouraging results have been obtained from our group on the possible use of rFVIIa (Novoseven). The general opinion is that there is no need for laboratory monitoring of the new antithrombotic agents. Conclusion. The research for safer and more effective anticoagulants has been successful by targeting specific steps in coagulation. These single-targeted agents are challenging multi-targeted drugs (heparins and vitamin-K antagonists). Other drugs including orally active FXa direct inhibitors will probably enrich the armentarium of antithrombotic drugs.