Atrial fibrillation (AF) has a prevalence of about 1% in the general population, but is much more common in the elderly. The annual overall risk of stroke is about 4.5% without antithrombotic therapy, but the risk in an individual patient varies from under 1% to about 20%, depending on the presence of well-recognized risk factors. The risk of stroke, usually followed by major neurological deficit or death, is reduced by about two-thirds by oral vitamin K antagonist (VKA) therapy and about 20% by aspirin. This risk reduction generally outweighs the risk of major hemorrhage caused by oral anticoagulation. New oral anticoagulants (dabigatran, rivaroxaban, and apixaban) obviate many of the difficulties experienced by patients and doctors in the use of oral VKAs. Comparisons with warfarin in recent large randomized clinical trials have demonstrated advantages of efficacy and safety, which vary somewhat from one agent to another but all offer excellent alternatives to VKAs for stroke prevention. Recent clinical practice guidelines recommend these agents as alternatives to VKAs.