Thromboembolic disorders continue to be a major cause of morbidity and mortality, resulting in an increased need for anticoagulant therapy. In recent years, new anticoagulant drugs have been developed at a rapid pace, prompted by the recognition of many undesirable properties of currently used agents, and by a greater knowledge of the active enzymatic sites of clotting factors. Furthermore, the structure of a thrombus is better understood, so that newer drugs can inhibit thrombin or Factor Xa not only on the surface of a thrombus, as in the case of heparin, but also the fibrin-bound thrombin or Factor Xa within the thrombus. These agents are usually small molecules synthesized on the basis of their inhibition of specific active sites in the respective coagulation factors. They possess many improved characteristics, such as greater efficacy and safety, oral administration, reliable pharmacokinetics, less need for laboratory monitoring and minimal interactions with other drugs and diet. Prominent among these are lepuridin (Refludan®, Pfizer), fondaparinux (Arixtra®, Sanofi-Synthelabo) and ximelagatran (Exanta®, Astra Zeneca). However, these new drugs are still far from fulfilling the desired objectives. Most of them possess some but not all of the needed properties. Furthermore, many do not have specific antidotes for immediate reversal of their pharmacologic actions, and all are much more costly than conventional agents. Development of newer agents with properties closer to that of the ideal drug remains a challenge.