Abstract The limits of traditional anticoagulants, such as heparin and warfarin, have prompted the search for new agents for prophylaxis and treatment of arterial and venous thromboembolism, including factor Xa and thrombin inhibitors. These agents can be given orally, and their most significant advantage is that no laboratory monitoring is needed. The anti-Xa inhibitor rivaroxaban and the direct thrombin inhibitor dabigatran etexilate are licensed for prophylaxis of venous thromboembolism (VTE) in high-risk orthopedic surgery. They are at least as safe and effective as heparins but much more expensive. Dabigatran, rivaroxaban, and other agents currently in the pipeline of clinical development have the potential to replace warfarin in the two most frequent indications for anticoagulation, i.e. secondary prophylaxis of VTE and atrial fibrillation. Prevention and treatment of coronary artery thrombosis in patients with ischemic heart disease is another area of investigation for the role of new anticoagulants. These drugs have the potential to meet some currently unmet needs of traditional anticoagulants, but available clinical data warrant confirmation and expansion. Lack of specific antidotes for anticoagulation reversal and the high cost are important limitations of their use.