Atrial fibrillation is the world's most common sustained cardiac arrhythmia and is associated with a significantly increased risk of stroke. The global burden of atrial fibrillation is rising, commensurate with the ageing population. Well-controlled vitamin K antagonist-based anticoagulation has been shown to reduce the risk of stroke secondary to atrial fibrillation by two-thirds. However, patients with atrial fibrillation have frequently been denied anticoagulation because of a variety of perceived risks related to bleeding, falls, chronological age, and poor compliance. Even when vitamin K antagonists are used, maximum benefit and safety are only delivered when high quality control of therapy (TTR>70%) is achieved, which has proven remarkably difficult in many health-care systems and amongst many patient groups. The non-vitamin K antagonist oral anticoagulants (NOACs) offer solutions to many of the challenges of achieving widespread, safe, and effective anticoagulation for stroke prophylaxis in atrial fibrillation, yet their uptake into routine clinical practice remains variable. The evidence supporting their more widespread use to overcome the challenges of stroke prophylaxis for atrial fibrillation is reviewed in this article.