Vitamin K antagonists have been the cornerstone of oral antithrombotic therapy to help prevent ischemic stroke in atrial fibrillation (AF) and reduce venous thromboembolic events. Despite proven clinical benefit, vitamin K antagonists have several limitations, including a narrow therapeutic window, slow onset/offset of action, need for close monitoring and significant drug/food interactions, highlighting the need for alternative therapies. Recently, the direct thrombin inhibitor dabigatran was approved by the US FDA for use in AF, and several factor Xa inhibitors are in late-stage clinical testing. Edoxaban is a novel, oral, reversible, direct factor Xa inhibitor with rapid absorption and predictable dose-dependent anticoagulation effects. Early clinical studies have shown promising results and it is currently undergoing large-scale Phase III trials for stroke prevention in AF and venous thromboembolic event prophylaxis and treatment. This review provides an overview of the current understanding, clinical trial results and pharmacology of edoxaban.