Direct oral anticoagulants (DOACs) have transformed the landscape of antithrombotic therapy in the past two decades. However, there is uncertainty about when they should or should not be used for treatment or prevention of thromboembolic events. DOACs have largely replaced warfarin for many patients with atrial fibrillation or venous thromboembolism who require anticoagulant therapy. In addition to noninferior efficacy, fewer drug–drug and food–drug interactions and improved convenience; DOACs have been shown to reduce the risk of intracranial hemorrhage. They have also received new indications compared with warfarin, such as cardiovascular risk reduction in patients with stable atherosclerotic diseases. However, there are some scenarios in which DOACs are associated with inferior efficacy or worse safety compared with standard treatment, such as warfarin. These include patients with mechanical heart valves, thrombotic antiphospholipid syndrome, and others. Although DOACs offer a streamlined and convenient option for the management of many patients with or at risk of thromboembolic events, their use should be avoided in certain high-risk scenarios. This minireview summarizes such conditions and those in which there is uncertainty for use of DOACs for particular diseases or particular patient subgroups.