Complications from atherosclerotic coronary artery disease are the principal cause of death worldwide. Many therapeutic strategies have been developed to reduce the burden of this disease. Systemic antithrombotic therapy, typically with unfractionated heparin, has long been a mainstay in the management of acute coronary syndromes (ACS) despite several limitations, including intravenous administration and unpredictable pharmacokinetics necessitating frequent monitoring. In recent years, newer agents without these limitations have been developed and evaluated in clinical trials. This review focuses on novel antithrombotic therapies for ACS, particularly fondaparinux sodium, a synthetic inhibitor of clotting factor Xa.