Atrial fibrillation (AF), the most common type of arrhythmia in adults, is a major risk factor for stroke. The prevalence of AF increases with age, occurring in 1% of persons <60 years of age and in almost 10% of those >80 years of age. Recent studies show that treatment strategies that combine control of ventricular rate with antithrombotic therapy are as effective as strategies aimed at restoring sinus rhythm. Current antithrombotic therapy regimens in patients with AF involve chronic anticoagulation with dose-adjusted vitamin K antagonists unless patients have a contraindication to these agents or are at low risk for stroke. Patients with AF at low risk for stroke may benefit from aspirin. Although vitamin K antagonists are effective, their use is problematic, highlighting the need for new antithrombotic strategies. This article will (a) provide an overview of the clinical trials that form the basis for current antithrombotic guidelines in patients with AF, (b) highlight the limitations of current antithrombotic drugs used for stroke prevention, (c) briefly review the pharmacology of new antithrombotic drugs under evaluation in AF, (d) describe ongoing trials with new antiplatelet therapies and idraparinux, and completed studies with ximelagatran in patients with AF, and (e) provide clinical perspective into the potential role of new antithrombotic drugs in AF.