Anticoagulant and antiplatelet drugs are used and studied in numerous trials for primary and secondary prevention of atherothrombosis since decades. The annual rate for cardiovascular morbidity and mortality is high in patients following an acute coronary syndrome and in patients with peripheral arterial disease (PAD) due to concomitant cardiac and cerebrovascular diseases. Plaque rupture and subsequent thrombosis involves activation of both platelets and coagulation factors. Therefore the combination of aspirin and warfarin to improve prevention of atherothrombosis compared to antiplatelet therapy alone was studied but could not be established due to significantly increased risk of major bleeding compared to a nonsignificant reduction in ischemic events. During the past two decades, clinical trials focused on combined antiplatelet therapies for the prevention of secondary events following acute coronary syndromes and very recently on the new oral anticoagulants in combination with antiplatelet therapy. This review discusses the role of the new oral anticoagulants such as Factor IIa (thrombin) and Factor Xa inhibitors in atherothrombosis, their pharmacological properties and recently published clinical data in secondary prevention of atherothrombotic events and potential implications for patients with PAD.