During the past five decades, anticoagulant therapy has consisted of rapidly acting parenteral drugs (unfractionated heparin [UFH] low-molecular-weight heparins [LMWH]) for prevention of venous thromboembolism and initial treatment of arterial and venous thromboembolism, whereas vitamin K antagonists (VKA) are used for longer term oral treatment. These drugs act by indirectly inhibiting several activated plasma clotting factors (UFH, LMWH) or by blocking the synthesis of some of them (VKA). In recent years, compounds that specifically block activated coagulation factor X (FXa) or thrombin have been developed. Thus, fondaparinux, and its long-acting derivative idraparinux, are administered subcutaneously. These substances inhibit F Xa indirectly via antithrombin. Small molecules have also been developed that directly block FXa (rivaroxaban, apixaban) or thrombin (dabigatran etexilate) following oral administration. In the present review we discuss the currently available evidence supporting the use of these new anticoagulants, in particular rivaroxaban and dabigatran etexilate, in the setting of thromboprophylaxis following major orthopaedic surgery, and the broader perspectives that these new drugs may open up in the next few years.