Direct oral anticoagulants (DOACs) are currently the first-choice therapy for the prevention of cardioembolic events in patients with atrial fibrillation and for the treatment of venous thromboembolism (VTE) due to their more favorable efficacy to safety profile in comparison to vitamin K antagonists (VKA). DOACs did not show a clinical benefit when used for in stroke prevention in patients with mechanic or rheumatic valves or in those who underwent transcatheter aortic valve implantation (TAVI), in the treatment of VTE in patients with antiphospholipid antibody syndrome and in prevention of VTE in medically ill patients. There are some concerns for bleeding excess at the gastrointestinal site for some, but not all, DOACs. In recent years, in order to overcome the limitations of the available DOACs and to explore the advantages of anticoagulation in additional clinical settings, the development of factor XI and factor XII inhibitors as anticoagulant agents has been proposed. Emerging data show that factor XI has a minor role in the physiological process of hemostasis and an important role in the development of thrombosis. Bleeding has been viewed for several years as an unavoidable side effect of anticoagulant therapy. The aim of factor XI inhibitors is to challenge this dogma by favoring the uncoupling between hemostasis and thrombosis. This paper provides an update on the rationale for the use of factor XI inhibitors, their pharmacological properties and the preliminary clinical findings.Copyright © 2023 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.