Antiplatelet medications are the agents of choice for secondary prevention of noncardioembolic ischemic strokes. Multiple clinical trials have proven their reliable albeit modest clinical benefits and relatively good safety profile. The most commonly recommended antiplatelet agents for secondary stroke prevention in North America and Europe are aspirin, clopidogrel, and the combination of aspirin and extended-release dipyridamole. Because of the multiple pharmacologic mechanisms available for platelet inhibition, combination antiplatelet agents have the potential for synergistic effects. However, combinations of antithrombotic agents do not necessarily improve clinical efficacy and are typically associated with increased toxicity. Clopidogrel and aspirin have been used in combination in patients with diverse arterial vascular diseases. Combination antiplatelet therapy with clopidogrel and aspirin has established clinical benefits, particularly in coronary disease and in patients who have undergone coronary stenting. Although it is tempting to extrapolate the benefits of clopidogrel and aspirin to the setting of secondary stroke prevention, recent clinical trials have failed to document significant clinical benefits in cerebrovascular patients. This failure has occurred because of a lack of significant efficacy for prevention of vascular events and a substantial increase in bleeding risk. Therefore, the clopidogrel and aspirin combination is not recommended for recurrent stroke prevention. In general, when clopidogrel is used for cerebrovascular patients, the addition of aspirin should be avoided unless there is a specific cardiac indication such as recent acute coronary syndrome or a coronary stent. The combination of aspirin and extended-release dipyridamole is supported by Class I data from two large studies demonstrating superiority over aspirin alone for recurrent stroke prevention. Although dual antiplatelet therapy with clopidogrel and aspirin has never been directly compared with the combination of aspirin and extended-release dipyridamole, clinical trial results favor the latter for secondary stroke prevention. Currently, there are no data for primary stroke prevention with dual antiplatelet agents regarding aspirin and extended-release dipyridamole. Limited data from the recent Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization Management and Avoidance (CHARISMA) trial indicate that the combination of clopidogrel and aspirin may be harmful, compared with aspirin alone.