Dabigatran, a direct thrombin inhibitor and 2 factor Xa inhibitors, rivaroxaban and apixaban, are target-specific oral anticoagulants (TSOACs) approved for prevention of stroke or systemic embolism in patients with nonvalvular atrial fibrillation (AF). Published data suggest that all 3 agents are at least as efficacious as dose‑adjusted warfarin in stroke prevention. Because of their greater specificity, rapid onset of action, and predictable pharmacokinetics, TSOACs have some advantages over vitamin K antagonists, which facilitates their use in clinical practice. The current review addresses the practical questions relating to the use of TSOACs in AF patients based on the available data and personal experience. We discuss topics such as patient selection, renal impairment, drug interactions, switching between anticoagulants, laboratory monitoring, and the risk of bleeding along with its management. We will focus on the aspects of the optimization of treatment with TSOACs in stroke prevention. The understanding of these practical issues by clinicians and patients is of key importance for the safe and effective use of TSOACs in everyday practice.