Atrial fibrillation (AF) is a supraventricular tachyarrhythmia (any tachycardic rhythm originating above the ventricular tissue) and is characterized by uncoordinated atrial activation with consequent deterioration of mechanical function. Different systems have been proposed to classify AF. Although the type of AF can change over time, it is often helpful to characterize it at a given moment, as this may guide treatment. Types of AF include first-detected, paroxysmal (arrhythmia terminates spontaneously within 7 days), persistent (arrhythmia is sustained beyond 7 days), longstanding persistent (usually lasting for more than 1 yr.), and permanent AF (in which cardioversion has failed or has not been attempted). The impact of AF is compounded by its known association with significant mortality, morbidity, and health care costs. Not only is the risk of death in patients with AF twice that of patients without AF, but AF can result in myocardial ischemia or even infarction, heart failure exacerbation, and tachycardia-induced cardiomyopathy if the ventricular rate is not well controlled. In some patients, AF can severely depreciate quality of life by causing shortness of breath, intractable fatigue, and near-syncope. However, the most dreaded complication of AF is thromboembolism, especially stroke. The risk of stroke in patients with AF is up to 8% per yr., depending on the presence of stroke risk factors. Importantly, when ischemic stroke occurs in patients with AF, it is either fatal or of moderate to high severity in the majority of patients. The management of AF and its complications is responsible for almost $16 billion in costs to the U.S. health care system each year. This review is designed to evaluate the comparative safety and effectiveness of a wide range of pharmacological and procedural rate- and rhythm-control strategies for the treatment of adult patients with paroxysmal, persistent, or permanent AF. The first three KQs focus on rate-control therapies: KQ1: What are the comparative safety and effectiveness of pharmacological agents used for ventricular rate control in patients with atrial fibrillation? Do the comparative safety and effectiveness of these therapies differ among specific patient subgroups of interest? KQ2: What are the comparative safety and effectiveness of a strict rate-control strategy versus a more lenient rate-control strategy in patients with atrial fibrillation? Do the comparative safety and effectiveness of these therapies differ among specific patient subgroups of interest? KQ3: What are the comparative safety and effectiveness of newer procedural and other nonpharmacological rate-control therapies compared with pharmacological agents in patients with atrial fibrillation for whom initial pharmacotherapy was ineffective? Do the comparative safety and effectiveness of these therapies differ among specific patient subgroups of interest? The next two KQs focus specifically on rhythm-control therapies: KQ4: What are the comparative safety and effectiveness of available antiarrhythmic agents and electrical cardioversion for conversion of atrial fibrillation to sinus rhythm? Do the comparative safety and effectiveness of these therapies differ among specific patient subgroups of interest? KQ5: What are the comparative safety and effectiveness of newer procedural rhythm-control therapies, other nonpharmacological rhythm-control therapies, and pharmacological agents for maintenance of sinus rhythm in atrial fibrillation patients? Do the comparative safety and effectiveness of these therapies differ among specific patient subgroups of interest? The final KQ seeks to evaluate the comparison of the available rate- and rhythm-control therapies: KQ6: What are the comparative safety and effectiveness of rate-control therapies versus rhythm-control therapies in patients with atrial fibrillation? Do the comparative safety and effectiveness of these therapies differ among specific patient subgroups of interest?