Stroke remains a leading cause of mortality and is associated with substantial morbidity in the United States. The majority of strokes are of ischemic origin, with an atherothrombotic trigger, and the clinical manifestation of atherothrombosis depends on the affected vascular site. The systemic nature of atherosclerosis means that stroke patients are at increased risk of ischemic events in several vascular beds, including cerebral, coronary and peripheral sites. Because stroke patients are at heightened risk of more ischemic events, secondary prevention is an important therapeutic goal. Recently, the American Heart Association and its division, the American Stroke Association, released new evidence-based guidelines for secondary stroke prevention in patients with ischemic stroke or transient ischemic attack. The new guidelines emphasize an individualized, patient-oriented approach to treatment based on clinical evidence. Evidence-based recommendations are set forth for the management of risk factors, including hypertension, dyslipidemia and diabetes, through lifestyle modifications and pharmacological interventions. The purpose of this paper is to review the topic of stroke prevention in light of current guidelines and clinical implementation patterns for primary care physicians, and to discuss new and emerging clinical evidence, with a focus on antiplatelet treatment.