High-quality epidemiologic studies have demonstrated that nonrheumatic atrial fibrillation (AF) is the most potent common risk factor for stroke, raising the risk of stroke five-fold, and that low-intensity anticoagulation can largely remove this risk. Six randomized trials of anticoagulation in AF consistently demonstrated a reduction in the risk of stroke by about two-thirds. In these trials, anticoagulation was quite safe. Other observations of anticoagulation have provided higher rates of hemorrhagic complications. On average, 100 individuals with AF have to take warfarin each year to prevent three strokes. To improve the benefit-to-risk ratio, investigators have conducted studies to find risk factors for stroke with AF and risk factors for major hemorrhage with anticoagulants, and have studied aspirin as an alternative preventive therapy. The analysis of the pooled data from the first set of randomized trials indicates that prior stroke, hypertension, diabetes, and increasing age are independent risk factors for future stroke with AF. Individuals younger than 65 with none of the other risk factors might safely avoid anticoagulation; for all others, anticoagulation seems indicated. Studies of hemorrhagic risk highlight the importance of keeping the international normalized ratio (INR) level under 4.0. Trials of aspirin have provided inconsistent results. Stroke due to AF is preventable. Translation of the results of the trials into clinical practice would be facilitated by: 1) identifying the lowest effective intensity of anticoagulation; 2) implementing more reliable systems for managing anticoagulation such as dedicated anticoagulation units; 3) more precisely measuring hemorrhagic risk with anticoagulation in representative populations with AF; and 4) incorporating technologically sophisticated measures into our assessment of the risk of stroke without treatment.