Atrial fibrillation is the most common cardiac arrhythmia responsible for one third of the hospitalizations because of cardiac rhythm disturbances. Atrial fibrillation leads to stroke, heart failure, and other causes of mortality. Warfarin, a vitamin K antagonist, is the first-line agent for the prophylaxis of stroke in patients with atrial fibrillation. Limitations associated with warfarin have led to development of new anticoagulants targeting different sites in the coagulation cascade. A direct thrombin inhibitor, dabigatran, has been evaluated in clinical studies for prophylaxis in atrial fibrillation. Factor Xa inhibitors, direct as well as indirect inhibitors, are in various stages of development for their antithrombotic effect. This article reviews the studies done on these novel anticoagulants and their prophylactic potential for the prevention of stroke in atrial fibrillation.