For most patients, direct oral anticoagulants (DOACs) are preferred over vitamin K antagonists for stroke prevention in atrial fibrillation and for venous thromboembolism treatment. However, randomized controlled trials suggest that DOACs may not be as efficacious or as safe as the current standard of care in conditions such as mechanical heart valves, thrombotic antiphospholipid syndrome, and atrial fibrillation associated with rheumatic heart disease. DOACs do not provide a net benefit in conditions such as embolic stroke of undetermined source. Their efficacy is uncertain for conditions such as left ventricular thrombus, catheter-associated deep vein thrombosis, cerebral venous sinus thrombosis, and for patients with atrial fibrillation or venous thrombosis who have end-stage renal disease. This paper provides an evidence-based review of randomized controlled trials on DOACs, detailing when they have demonstrated efficacy and safety, when DOACs should not be the standard of care, where their safety and efficacy are uncertain, and areas requiring further research. Display omitted •Target-specific (or direct) oral anticoagulants are preferred for prevention or treatment of thromboembolism in most patients with atrial fibrillation or venous thromboembolism.•DOACs should not be the standard treatment for patients with mechanical heart valves, atrial fibrillation with rheumatic mitral stenosis, or antiphospholipid syndrome.•The efficacy and safety of DOACs remain uncertain for several other clinical conditions and subgroups, and future studies should address those situations.