Randomized trials have demonstrated that warfarin is effective for stroke prevention in patients with atrial fibrillation (AF), yielding relative risk reductions for ischemic stroke of nearly 70%. However, successful use of warfarin requires frequent monitoring and dose adjustment to maintain an international normalized ratio (INR) within the range of 2.0 to 3.0. Many clinicians and patients have been reluctant to use warfarin therapy in AF, with underuse generally attributed to the inconvenience of INR monitoring, complexities of drug and dietary interactions associated with warfarin, and perceived bleeding risk. The ensuing search for safe, effective alternatives with a lower associated risk of bleeding and no need for monitoring and dose adjustment has focused attention on more specific inhibitors of the clotting cascade, such as factor Xa inhibitors or direct thrombin inhibitors. The direct thrombin inhibitor dabigatran has recently been approved by the US Food and Drug Administration for the prevention of stroke in patients with AF. New factor Xa inhibitors apixaban, rivaroxaban, and edoxaban are also currently being studied in stroke prevention trials in patients with AF to determine their comparability with warfarin. It is anticipated that fixed-dose administration of these new oral agents will provide effective anticoagulation without the need for frequent monitoring and with a lower risk of bleeding events.