In patients with atrial fibrillation (AF) warfarin has been the mainstay therapy for stroke prevention. In recent randomized clinical trials (RCTs) oral direct thrombin inhibitor (Dabigatran) and factor Xa inhibitors (Rivaroxaban and Apixaban) challenged the efficacy and safety benchmarks set by warfarin. These drugs boast a rapid onset of action, shorter half-life and fewer drug and dietary interactions. Moreover, these new anticoagulants do not require monitoring, titration or dose adjustments. These agents have already been approved for prevention of stroke or systemic embolism in patients with AF. Uncertainty regarding suitability, efficacy and safety in certain patient subsets and issues related to the ability effectively monitor the pharmacodynamic effects and reverse the therapeutic effects of these drugs should be addressed as we engage in a widespread use of these agents in various patient subsets.