Although Coumadin® (warfarin) has been the standard outpatient anticoagulant for long-term prevention of thrombosis for many decades, it presents with significant challenges for both patients and health care providers in optimizing standards of care including dietary and drug restrictions, regular monitoring of the patient's International Normalized Ratio (INR), and difficulty maintaining therapeutic levels. Despite its unmistakable effectiveness, there has been an interest from the medical community in developing potential alternative drug therapies. As a result, within the past three years the U.S. Food and Drug Administration (FDA) has approved the use of three new oral anticoagulant drugs (dabigatran, rivaroxaban, and apixaban) specifically targeting thrombin or factor Xa that have overcome many of the barriers seen in warfarin therapy. The use of these new oral anticoagulants is of particular interest in patients who have failed warfarin therapy or for whom warfarin therapy is contraindicated, in situations when monitoring is not feasible or interactions are problematic, or if patient INR control is poor. All of these novel agents are currently approved for prevention of thrombosis in patients with nonvalvular atrial fibrillation, and with ongoing clinical research these agents may present health care providers with additional therapeutic options in a greater variety of disease states. For the comparative purposes of this article, we have combined all of the recent clinical evidence and major landmark trials for each of these new agents as well as benefits and drawbacks of therapy in specific patient populations when compared to warfarin.