Antithrombic therapy is recommended to prevent ischemic complications in patients with high-risk non-ST-segment elevation acute coronary syndromes, including patients with unstable angina/non-ST-segment elevation myocardial infarction and patients with ST-segment elevation myocardial infarction undergoing fibrinolysis with fibrin-specific agents. Ischemic benefit from these agents must be balanced against an increased risk of bleeding, which may itself carry adverse long-term consequences. Recent trials suggest that the low-molecular-weight heparin enoxaparin may be superior to unfractionated heparin for preventing ischemic complications, although it also may be associated with an increase in bleeding risk. In two other contemporary trials, the Factor Xa inhibitor fondaparinux improved mortality and morbidity in patients with unstable angina/non-ST-segment elevation myocardial infarction and in patients with ST-segment elevation myocardial infarction undergoing fibrinolytic reperfusion, without increasing bleeding risk. These data underscore the promise of new antithrombotic agents to improve outcomes in acute coronary syndrome (ACS) patients being medically managed.