Vitamin K antagonists (VKA) have been the primary anticoagulant for the past few decades, and to a lesser degree aspirin, in preventing thrombotic events from atrial fibrillation. In spite of our experience with warfarin over the years, its use has been limited by multiple challenges: its need for frequent international normalized ratio (INR) monitoring, its narrow therapeutic range, variation with metabolism, diet, and other medications, and the need for frequent dosage adjustment. With the advent of newer/novel oral anticoagulants such as oral direct thrombin inhibitors (dabigatran) and oral factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban), we are at the dawn of a new era in anticoagulation. Compared with VKAs, they do not need INR monitoring, have a rapid onset of action, are a fixed-dose therapy, and for unclear reasons, have been shown to cause significantly less intracranial hemorrhage than VKAs.