Randomized clinical trials have conclusively demonstrated that warfarin prevents stroke in patients with atrial fibrillation. This evidence led the American College of Cardiology, the American Heart Association, and the European Society of Cardiology to designate warfarin as a Class I indication in patients at moderate to high risk for stroke. Despite the evidence from randomized clinical trials and clear practice guidelines, warfarin is underutilized in many eligible patients. This is, at least in part, due to the many challenges associated with warfarin use that have led to the development of many new anticoagulants including direct thrombin inhibitors and factor Xa inhibitors. In this article, we review the complexities of anticoagulation in patients with atrial fibrillation, underscoring the challenges related to warfarin use, and present an overview of new anticoagulants particularly, factor Xa inhibitors, with special emphasis on emerging data from randomized clinical trials on their efficacy and safety in the management of atrial fibrillation.