Patients undergoing surgery for total hip arthroplasty (THA) or total knee arthroplasty (TKA) are at particularly high risk for developing venous thromboembolism (VTE). Despite the existence of effective therapies for VTE prevention, THA/TKA patients remain at risk for developing thrombi. Furthermore, the incidence of VTE is predicted to increase as an aging and increasingly obese population experiences joint damage necessitating THA and TKA. Current guidelines recommend the use of a wide range of antithrombotic agents in patients undergoing THA and TKA. These agents include vitamin K antagonists, low-molecular-weight heparins, fondaparinux, and the new oral anticoagulants. However, adherence to guidelines in clinical practice is disappointingly low. The limitations of traditional anticoagulants present management challenges following orthopedic surgery. Vitamin K antagonists present a number of drawbacks, including a narrow therapeutic window and unpredictable pharmacokinetics and pharmacodynamics. The subcutaneous route of administration of fondaparinux and low-molecular-weight heparins may make them unacceptable to patients in the outpatient setting. The introduction of a new generation of anticoagulants promises to address many of the drawbacks associated with the traditional agents. Clinical studies have shown the new oral anticoagulants to be as effective as traditional thromboprophylaxis, with good tolerability profiles. Clinical knowledge of these new agents will be essential to ensure that patients receive appropriate care following orthopedic surgery. This article will discuss the prevention of VTE after THA and TKA based on current evidence-based practice guidelines, the limitations of conventional anticoagulants, and the promise of new therapeutics.