Venous thromboembolism is a serious, frequent, and potentially fatal complication of major orthopedic surgery. Currently available pharmacologic agents for the prevention of venous thromboembolism in this high-risk population consist of the oral anticoagulants and the heparin family of antithrombotic agents (unfractionated heparin, low-molecular-weight heparin, heparinoids). These classes of agents interfere with the activity of both thrombin and factor Xa (or their respective zymogens) to varying degrees. Newer antithrombotic agents in various stages of development exert their antithrombotic effect through a more targeted mechanism of action. Direct factor Xa inhibitors and the newest class of antithrombotic agents, the indirect factor Xa inhibitors, the prototype of which is the synthetic pentasaccharide fondaparinux sodium, limit fibrin formation through their exclusive inactivation of factor Xa. Clinical data from venous thromboembolism prophylaxis trials in hip and knee replacement and hip fracture surgeries, including the recently completed fondaparinux phase II and phase III trials, indicate that selective antifactor Xa activity may improve the efficacy:safety ratio of antithrombotic therapies for the prevention of venous thromboembolism in high-risk major orthopedic surgery.