Vitamin K antagonists have been the standard in stroke prophylaxis in patients with atrial fibrillation for decades, but several limitations make it difficult for patients to tolerate chronic anticoagulation treatment. New drugs are under evaluation in clinical trials, including direct thrombin inhibitors and factor Xa inhibitors. Antiplatelet agents such as clopidogrel and aspirin are alternatives to warfarin for stroke prevention but have proven less efficacious in trials. The only drug to have completed a Phase III trial successfully thus far is dabigatran. The 150-mg twice-a-day dose was superior to warfarin in efficacy and similar for major bleeding, whereas the 110-mg twice-a-day dose was noninferior for efficacy and reduced major bleeding. Both doses reduced intracranial hemorrhages substantially compared with warfarin. Dabigatran-assigned patients had a higher incidence of discontinuation due to gastrointestinal symptoms. Clinically apparent myocardial infarction rates were slightly higher in the dabigatran groups than the warfarin group. Dabigatran is the first agent to show superiority over warfarin for stroke prevention in atrial fibrillation, raising the standard for newer agents.