As one of the most powerful independent risk factors for ischemic stroke and the most clinically relevant arrhythmia, atrial fibrillation (AF) poses a serious clinical and public health threat as the global population ages. AF increases the risk of ischemic stroke 4- to 5-fold although this statistic varies with age of the patient. Indeed, the prevalence rises to 1 in 25 people aged > or =60 years and 1 in 10 people aged > or =80 years. More than 2.3 million Americans have diagnosed AF, and that number is expected to increase dramatically over the coming decades. Ischemic stroke causes the most major disability and remains the third leading cause of death in the United States. Therapeutic strategies and optimal risk stratification offer the best hope for decreasing the burden of AF-related thromboembolism. This article focuses on the randomized trial evidence for the efficacy and safety of oral vitamin K antagonists (eg, warfarin) for stroke prevention in AF. In particular, this article explores how well these findings translate into clinical practice, especially among patients with AF treated outside of clinical trials. Discussion centers on using evidence-based data to guide treatment for patients who are at increased risk for stroke. Such strategies would enhance the net benefit of oral anticoagulation. Concluding points provide information on improving risk stratification for stroke in patients with AF.