In the past few years, the clinical field of anticoagulation has undergone dramatic changes due to the introduction of the new class of direct oral anticoagulants. All these agents share common features such as stable oral bioavailability, short half-life compared to vitamin K antagonists, paucity of drug-drug interactions, and fixed dosing without laboratory monitoring. However, the new agents differ regarding metabolism pathways, impact on routine clotting tests, availability of test systems for plasma concentration, and-of utmost clinical importance-dose regimens, clinical evidence, and approved indications.The present review outlines pharmacologic properties, clinical indications, different dose regimens, and preliminary clinical experience from their use in daily practice. Each of the four topics will be complemented by a compilation and in-depth discussion of open questions and lessons still to learn. The well-documented benefits of the direct oral anticoagulants as documented in clinical trials will translate to routine clinical practice only if all the rules regarding dosing and indications are obeyed, and if the experience with these agents is captured and communicated in a controlled manner.