The advantages of dual antiplatelet therapy over monotherapy in preventing recurrent ischemic events are examined. Atherosclerosis is an insidious systemic process involving multiple vascular beds, including the cerebral, coronary, and peripheral arteries. Atherosclerotic plaque rupture is one of the inciting events in the progression of platelet activation, aggregation, and thrombus formation. Patients with any clinical manifestation of atherosclerosis are vulnerable to others in different vascular beds since the disease develops throughout the vasculature, and different vascular events have common predisposing risk factors. Ischemic coronary heart disease and cerebrovascular disease are two of the three most frequent causes of death in the United States. The efficacy of aspirin in the secondary prevention of myocardial infarction (MI) and stroke has been demonstrated in numerous trials. While dipyridamole has not been linked with a greater odds reduction than aspirin in the development of MI, stroke, and vascular death, ticlopidine and clopidogrel have been associated with a greater reduction in the development of acute MI, stroke, and vascular death than aspirin. Clinical trials evaluating the efficacy and safety of combination antiplatelet therapy in the prevention of recurrent ischemic events are ongoing. The rationale for using a combination of two mechanistically different antiplatelet agents is supported by ex vivo and clinical studies. Inhibition of platelet aggregation and thrombus formation is enhanced with dual antiplatelet therapy. Combination antiplatelet regimens with different mechanisms of action to inhibit multiple sites in the thrombotic pathway may further improve long-term clinical outcomes. Dual antiplatelet therapy may have advantages over monotherapy in the prevention of recurrent ischemic events.