Until recently, warfarin had been one of the only treatment options for long-term anticoagulation of patients with atrial fibrillation, venous thromboembolism, or other medical conditions that require chronic anticoagulation. A main concern when treating patients with anticoagulants is balancing the benefits of preventing a thromboembolic event with the risks of bleeding events. The US Food and Drug Administration recently approved 2 new oral anticoagulants, dabigatran and rivaroxaban, for stroke prevention in patients with atrial fibrillation, and is currently reviewing a drug application for a third new oral anticoagulant, apixaban. These new anticoagulants do not require strict and frequent laboratory monitoring, dosing adjustments, or dietary restrictions, and they incur fewer drug-drug interactions than warfarin. However, these new medications do not have specific reversal agents, may require dosage adjustment based on patient renal function, and lack clinical data regarding their long-term safety and efficacy. The 2012 American College of Chest Physicians Evidence-Based Clinical Practice Guidelines for antithrombotic therapy and prevention of thrombosis include recommendations for dabigatran, rivaroxaban, and apixaban for certain indications. Each of the 3 novel oral anticoagulants has specific pharmacokinetic and pharmacodynamic properties that may make them suitable agents for use in specific patient populations. Knowledge of dosing, drug-drug interactions, monitoring parameters, and clinical considerations for each of these new medications will help clinicians decide for which patients they may be best suited to replace conventional therapy with warfarin.