Atrial fibrillation (AF) is a major risk factor for stroke and systemic embolization, particularly in the elderly. Approximately 2.3 million adults in the United States have AF, and it is projected that this number will increase to approximately 5.6 million individuals by the year 2050, with over 50% aged 80 years or older. Vitamin K antagonists are currently the most widely accepted means of stroke prevention in patients with AF; unfortunately, this method of treatment is not a feasible option for many patients for numerous reasons. This article examines and compares the various newer therapeutic agents that have either been approved by the US Food and Drug Administration or are still in various stages of clinical testing, and provides an overview of established antithrombotic therapies. We also discuss the role of anticoagulation in the setting of cardioversion in patients with AF.