Since 2010, four new direct oral anticoagulants (DOACs) have emerged from phase III clinical trials that establish their safety and efficacy for the prevention and treatment of thromboembolism in several different clinical settings. These agents are a welcome addition to the previously shorter list of choices for chronic anticoagulant therapy. Although they offer a number of possible advantages compared with vitamin K antagonists, their novel mechanisms of action and their unique characteristics mandate that healthcare providers who prescribe these agents thoroughly understand their pharmacology, their indications, and the considerations in clinical practice, about which more research is needed.