In patients with non-valvular atrial fibrillation (NVAF), oral anticoagulation is important for prevention of stroke and systemic embolism (SE). While Vitamin K antagonists (VKAs) have historically been the standard of care, these medications are limited by numerous food and drug interactions with onerous requirements for frequent monitoring and dose adjustments. Over the past decade, several novel oral anticoagulants (NOACs) have been developed to directly inhibit factor IIa/thrombin (dabigatran) or activated factor X (apixaban, rivaroxaban, edoxaban). These medications have been shown to be at least as effective as warfarin for stroke prevention in NVAF with more favorable safety profiles. However, their advantages are underscored by a lack of specific antidotes and assays quantifying their anticoagulant effects. This paper addresses the use of NOACs compared to VKAs in patients with NVAF, with a special focus on high-risk populations, including the elderly, those with renal disease, diabetes mellitus, coronary artery disease, and previous stroke. The current literature surrounding special clinical scenarios including the treatment of bleeding, perioperative management, and the use of NOACs in cardioversion and catheter ablation will be also discussed.