Anticoagulation therapy (AT) is fundamental in atrial fibrillation (AF) treatment but poses challenges in implementation, especially in AF populations with elevated thromboembolic and bleeding risks. Current guidelines emphasize the need to estimate and balance thrombosis and bleeding risks for all potential candidates of antithrombotic therapy. However, administering oral AT raises concerns in specific populations, such as those with chronic kidney disease (CKD), coagulation disorders, and cancer due to lack of robust data. These groups, excluded from large direct oral anticoagulants trials, rely on observational studies, prompting physicians to adopt individualized management strategies based on case-specific evaluations. The scarcity of evidence and specific guidelines underline the need for a tailored approach, emphasizing regular reassessment of risk factors and anticoagulation drug doses. This narrative review aims to summarize evidence and recommendations for challenging AF clinical scenarios, particularly in the long-term management of AT for patients with CKD, coagulation disorders, and cancer.Copyright © 2024 Elsevier Ltd. All rights reserved.