Antiplatelet agents (APA) are used to reduce the risk of major cardiovascular events in various settings. When used for secondary prevention, antiplatelet monotherapy is associated with a relative risk reduction of such ischemic events of 25% compared to a placebo. New strategies are based on dual APA therapy. Aspirin-clopidogrel combination therapy is effective in situations of acute vessel injury such as myocardial infarction, coronary stenting and, possibly, peripheral stenting. GPIIb/IIIa inhibitors and loading doses of clopidogrel also have a place in these acute settings. In contrast, the aspirin-clopidogrel combination has proven disappointing in stable patients with cardiovascular disease, with no beneficial effect and, often, more bleeding events. Combination therapy with aspirin and extended-release dipyridamole may be more beneficial than very low doses of aspirin in ischemic stroke, but its use is limited by adverse effects. Overall, aspirin remains the first-line monotherapy of choice for patients with atherothrombosis, while clopidogrel is a valuable alternative. New antiplatelet strategies are in the pipeline, and clinically relevant laboratory tests of APA response may soon help to tailor treatment.