Anticoagulant therapy is widely used for the management of acute coronary syndromes. In order to optimize patient outcomes, anticoagulants should ideally combine high antithrombotic efficacy with a low risk of bleeding. Intravenous unfractionated heparin has been in clinical use for more than 50 years and reduces the risk of recurrent ischemic events in patients with acute coronary syndromes but at the cost of increased bleeding. Enoxaparin, compared with intravenous unfractionated heparin, further reduces the risk of ischemic events but also increases bleeding. Neither of these approaches has been shown to reduce mortality. The synthetic parenteral Factor Xa inhibitor, fondaparinux, is highly effective for the prevention and treatment of venous thromboembolic disease in medical and surgical patients. The Organization for the Assessment of Strategies for Ischemic Syndromes (OASIS) 5 and 6 trials evaluated the efficacy and safety of fondaparinux in more than 32,000 patients with non-ST elevation acute coronary syndromes or ST elevation myocardial infarction. This clinical trial report discusses the findings of these two pivotal trials.