Atrial fibrillation (AF) is a highly prevalent cardiac arrhythmia associated with an increased risk of stroke. The role of anticoagulation therapy in the prevention of thrombosis and stroke is of critical importance for patients with AF. Limitations with vitamin K antagonists (VKAs), the current standard of care, have led to the development of novel oral anticoagulants (NOACs) that target either thrombin (dabigatran etexilate) or activated factor X (rivaroxaban, apixaban, and edoxaban). In comparison with traditional VKAs such as warfarin, these NOACs offer several pharmacologic advantages, including rapid onset of action, no significant food interactions, low potential for drug-drug interactions, and no requirement for routine coagulation monitoring. Completed phase-III clinical trials have demonstrated the therapeutic potential of dabigatran, rivaroxaban, and apixaban in comparison with warfarin for stroke prevention in patients with nonvalvular AF (NVAF). While the future utility of NOACs in preventing stroke in patients with NVAF looks promising, several practical issues, including the current lack of a reversal strategy and use of these agents in older patients with renal dysfunction, must be considered. Clinician and patient understanding of such issues will be important for the safe and effective use of NOACs.