Atrial fibrillation is the most common cardiac arrhythmia encountered in clinical practice, and with a rapidly increasing prevalence and incidence, it will reach epidemic levels. Embolic stroke is the feared and devastating complication that results in significant mortality, morbidity, and burden to the public health sector. Vitamin K antagonists, such as warfarin, have been the only class of oral antithrombotics used for over 50 years for the prevention of stroke and systemic embolism in patients with atrial fibrillation. Unfortunately, these drugs have a narrow therapeutic window that requires frequent monitoring due to unpredictable pharmacokinetics secondary to common genetic differences and multiple food and drug interactions. There are now several promising novel oral antithrombotics in late stages of clinical development that offer a promise of safer and more convenient anticoagulation.