Thrombotic events contribute significantly to the morbidity, mortality, and health care costs of patients undergoing major orthopedic surgery. Despite therapy with unfractionated heparin, low-molecular-weight heparin, or warfarin, thrombotic events continue to occur at an unacceptably high rate in populations at risk. The need for improved prophylaxis against venous thromboembolism has resulted in the development of several new antithrombotics, both recently approved and investigational, that target specific steps in the hemostatic pathway. These include direct thrombin inhibitors, agents that inhibit the factor VIIa-tissue factor complex, and selective factor Xa inhibitors. Fondaparinux is the first of the selective factor Xa inhibitors. It was evaluated in the most comprehensive drug development program ever in major orthopedic surgery, culminating in four phase III trials involving more than 7000 enrollees, and is the first agent in its class to be approved by the U.S. Food and Drug Administration and the European Agency for the Evaluation of Medicinal Products. It has been suggested that fondaparinux's superior efficacy may be related to its ability to initiate selective inhibition of factor Xa and its predictable linear pharmacokinetics.