The prevalence of atrial fibrillation (AF) continues to increase worldwide, largely affecting the elderly, but also occurring in younger patients as a result of structural heart disease, autonomic imbalance, genetic abnormality, or previous cardiac surgery. Despite major advances in the understanding of the diverse pathogenesis, electrophysiological mechanisms, and triggering factors contributing to AF, the management of this arrhythmia is still palliative in most cases. It consists of anticoagulation prophylaxis and pharmacological therapy aimed at either maintenance of sinus rhythm or merely ventricular rate control and lifelong anticoagulation. Sinus rhythm can relieve symptoms, improve cardiac function, and theoretically lessen the risk of thromboembolic events. However, prophylactic antiarrhythmic drug therapy has limited efficacy and is associated with a significant risk for proarrhythmias or noncardiac adverse effects. These limitations of antiarrhythmic drugs have led to the development of nonpharmacological approaches such as the dualchamber atrial pacemaker or defibrillator and surgical and catheter ablation techniques. Despite all these advances, a successful curative therapy for AF is, however, relatively unusual, and preventative therapies are rarely contemplated. A fundamental question is whether “upstream” therapy of the causes of AF may increase the likelihood of successful treatment. Prevention of AF is an attractive possibility that will rely on general prevention of cardiac disease, identification of those at risk of AF, and the development of specific therapeutic strategies to prevent the evolution of an electrophysiological milieu that will support the arrhythmia...