Nurses and nurse practitioners play an integral role in initiating and managing antithrombotic prophylaxis in patients with atrial fibrillation (AF). Since the advent of warfarin in the 1950s, there have been few changes in this field until recently. Warfarin has been used for decades and has well-demonstrated efficacy. However, it also has well-known drawbacks, including an unpredictable dose response, need for anticoagulation monitoring, frequent dose adjustments, and many drug and food interactions. A new generation of anticoagulants, which includes direct thrombin inhibitors and selective Factor Xa inhibitors, shows the potential to significantly improve options for antithrombotic prophylaxis and to positively affect patient outcomes. The objective of this review is to update nurses on the new oral anticoagulants, other recent developments, such as improved risk-assessment techniques, and the role of over-the-counter products, including aspirin.