Atrial fibrillation (AF) is the most commonly encountered arrhythmia in clinical practice and is associated with substantial morbidity and mortality. Its prevalence increases with age, affecting about 1% of patients aged <60 years and almost 10% of patients >80 years. AF is associated with a fivefold increasing risk of embolism or stroke with absolute risk ranging from less than 1% to 20% per year, depending on patient age and the presence of clinical risk factors including congestive heart failure, systemic hypertension, diabetes mellitus and prior history of cardioembolic events. Vitamin K antagonists (VKAs) and acetyl salicylic acid are currently the only licensed antithrombotic therapies for stroke prevention in patients with AF. Anticoagulants are very effective for stroke prevention in patients with AF, overall a 64% relative risk reduction. Nonetheless, approximately 50% of patients with AF who have an indication for VKA receive anticoagulant therapy, of which only 50% maintain adequate therapeutic ranges. Furthermore, 50% will discontinue VKAs within 3 to 5 years regardless of appropriate international normalized ratio control. Underutilization of VKAs is related, in part, to their numerous limitations and difficulty in maintaining adequate therapeutic control, prompting the development of new antithrombotic strategies that are equally effective and safer, and easier to manage than VKAs. This review focuses on new antithrombotic therapies for stroke prevention in patients with AF.