This review article evaluates novel oral anticoagulants in comparison with warfarin for thromboembolism prophylaxis in patients with atrial fibrillation (AF). AF is the most frequently diagnosed arrhythmia in the United States. The most serious side effect of AF is stroke. Warfarin has several decades of proven efficacy in AF-related stroke prevention but the drug's numerous drawbacks make its implementation difficult for practitioners and patients. The difficulties of warfarin have prompted the development of alternative anticoagulants for AF-related stroke prevention with better efficacy, safety, and convenience. The oral direct thrombin inhibitor, dabigatran, and the oral factor Xa inhibitors, rivaroxaban and apixaban, have been evaluated in a large phase III trial. Dabigatran, rivaroxaban and apixaban were shown to be noninferior compared with warfarin in the prevention of stroke. Dabigatran and apixaban were found to be statistically superior to warfarin. All three may also have a better safety profile than warfarin. In conclusion, novel anticoagulants have a different pharmacologic profile compared with warfarin that may eliminate many of the treatment inconveniences. Practitioners must also be aware of the disadvantages these new drugs possess when choosing a management strategy for their patients. Drug selection may become clearer as these new drugs are used more extensively.