Patients with atrial fibrillation (AF) face an elevated risk of stroke compared with patients who have normal sinus rhythm. Warfarin, an oral vitamin K antagonist, is a highly effective therapeutic agent to reduce stroke risk in patients with AF; however, use of warfarin is complicated by variable patient dose response due to genetic factors and multiple food-drug and drug-drug interactions. Novel oral anticoagulants appear to be a safe, effective alternative to warfarin therapy without the need for routine coagulation monitoring. Dabigatran, a direct thrombin inhibitor, has been commercially available since 2010 for prevention of stroke in patients with nonvalvular AF. More recently, the US Food and Drug Administration (FDA) approved 2 oral activated factor X inhibitors, rivaroxaban and apixaban, for stroke prevention in patients with AF based on clinical trial evidence of their safety and efficacy. In this article, we provide an overview of the 3 novel oral anticoagulants for treating patients with AF and discuss the latest findings from subgroup analyses.