Despite advances in diagnosis, prevention, and management, venous thromboembolism (VTE) remains a common cause of morbidity and mortality. For decades, antithrombotic therapy for prevention and treatment of VTE was limited to parenteral agents related to heparin and oral vitamin K antagonists (VKAs). Both classes of anticoagulants are effective, but have limitations, including considerable variability in dose-response, narrow therapeutic margins between the risks of thrombosis and bleeding, and the need to monitor anticoagulation intensity. Over the past decade, the introduction of new oral anticoagulants that specifically inhibit coagulation factors IIa (thrombin) or Xa has changed practice in a variety of clinical situations, including VTE prophylaxis and treatment. In this Review, we outline the use of the novel oral anticoagulants apixaban, dabigatran, edoxaban, and rivaroxaban in the prevention and treatment of VTE, and discuss practical considerations for choosing the appropriate drug for each patient. Although the introduction of novel anticoagulant drugs is promising, selecting the optimum strategy for an individual patient requires an understanding of the specific circumstances associated with thrombus formation and the pharmacological properties of each agent.