Although cardiovascular disease (CVD) is a major source of morbidity and mortality in the United States, a relatively small percentage of deaths related to CVD result from ischemic stroke. However, the impairment and costs associated with stroke are large-and largely preventable. Large-scale trials have demonstrated benefit with antihypertensive therapy for secondary prevention, showing significantly reduced rates of stroke and cardiovascular events. Statins have shown efficacy in primary stroke prevention, and one trial showed reduced incidence of stroke and cardiovascular events in patients with recent stroke or transient ischemic attack (TIA). The merits of antiplatelet therapy in primary and secondary stroke prevention have been demonstrated across numerous trials and meta-analyses. Trials assessing aspirin plus clopidogrel or aspirin plus extended-release dipyridamole for preventing secondary stroke have produced somewhat contradictory findings. This review discusses the relationship between CVD and risk of secondary stroke or TIA and summarizes secondary prevention strategies, focusing on antiplatelet agents, to provide guidance for the practicing cardiologist. Certain combination therapies appear to be more effective for secondary prevention of stroke or TIA than therapy with single antiplatelet agents. The choice of agents may be important, based on results of several trials. The ongoing, large-scale, comparative Prevention Regimen for Effectively Avoiding Second Strokes (PR. FESS®) trial should provide cardiologists with more definitive recommendations.