The new oral anticoagulants may prove to be one of most significant innovations in clinical practice in the past 60 years. Apixaban and rivaroxaban are direct inhibitors of Factor Xa, while dabigatran inhibits Factor IIa. The predictable pharmacological profile of these new agents allows physicians to prescribe these drugs without the need for routine coagulation monitoring, which is the mainstay of warfarin therapy. In addition, these new agents have not been shown to have any food interactions and minimal drug–drug interactions, interactions are limited to the p-glycoprotein (p-Gp) transporter or cytochrome P450 (CYP450) system, each drug is unique in its drug interaction profile, as will be discussed below. These unique pharmacokinetics profiles may usher in for clinicians a new era of managing thromboembolic disorders. In this article, the pharmacology of these new oral anticoagulants will be reviewed along with the major clinical trials evaluating the use of these agents for thromboembolic prophylaxis in patients undergoing total hip and knee arthroplastic surgery, the treatment of venous thromboembolic disorders and stroke prevention in atrial fibrillation. Am. J. Hematol., 2012. © 2012 Wiley Periodicals, Inc.