Atherothrombosis is responsible for most acute ischemic manifestations of atherosclerotic disease, including stroke. Individuals with evidence of atherothrombotic disease in one vascular bed have a significant risk of recurrence and show increased vulnerability over time for other manifestations elsewhere in the vasculature. Ischemic event rates for asymptomatic patients with multiple atherothrombotic risk factors appear to be similar to those in patients with documented cardiovascular disease. For example, diabetes mellitus and obesity are found at alarmingly high rates in patients with prior cardiovascular events, including stroke or transient ischemic attacks. Antiplatelet therapy is a key component of atherothrombotic event prevention. The results of the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance (CHARISMA) study showed that while dual antiplatelet therapy with aspirin and clopidogrel may not play a role in primary prevention, post hoc analysis alluded to the possibility of benefit for dual antiplatelet therapy in certain populations of stroke patients. We examined current recommendations for the prevention of atherothrombotic events, focusing on the role of oral antiplatelet agents in patients with ischemic stroke.