Cardiovascular disease is prevalent among patients with stroke; thus, cardiologists frequently treat patients at high risk for stroke. Results from recent clinical trials of antiplatelet medications, given alone or in combination, may be of special interest to cardiologists. The MATCH study demonstrated no significant difference between clopidogrel alone and clopidogrel plus aspirin in reducing risk of vascular events after stroke or transient ischemic attack. A 1.3% increased risk of major bleeding was associated with clopidogrel plus aspirin. In CHARISMA, clopidogrel plus aspirin did not reach statistical significance vs. placebo plus aspirin in reducing incidence of myocardial infarction (MI), stroke, or death from cardiovascular causes in patients with stable atherothrombotic disease; clopidogrel was associated with an increase in moderate bleeding. These results suggest that clopidogrel plus aspirin may be inappropriate as first-line therapy for secondary stroke prevention. In patients with established cardiovascular disease at risk for MI or other vascular events, physicians must weigh the benefits and risks before choosing this therapy. Selection of an antiplatelet agent must be based on patient history, including previous MI and stroke, susceptibility to bleeding, and other high-risk factors (e.g. advanced age and diabetes). Aspirin plus extended-release dipyridamole may be more effective than clopidogrel for preventing stroke in high-risk patients. This article strives to put MATCH and CHARISMA results into context by providing an overview of antiplatelet therapy, including relevant clinical trial results, a review of current practice guidelines, and a summary of an ongoing study that will improve clinical decision making.