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Thrombosis remains one of the leading causes of death worldwide. The history of anticoagulation has evolved considerably, from non-specific drugs (i.e., heparins and vitamin K antagonists [VKAs]) to molecules that directly target specific coagulation factors (i.e., argatroban, fondaparinux, and direct oral anticoagulants [DOACs]). Over the past decade, DOACs have been widely used in clinical practice because of their ease of use, favorable pharmacological profile, and lack of need for laboratory monitoring. However, despite having a better safety profile than VKAs, their risk of causing hemorrhagic events remains and is a feared side effect. New anticoagulants targeting the contact phase of coagulation are currently being developed and could potentially prevent the risk of thrombosis without impairing physiological hemostasis, thereby reducing the bleeding risk. Observational and preclinical data on factor XI (FXI) deficiency make FXI a promising therapeutic target. The aim of this review is to summarize the results of the various clinical trials available that focus on FXI/FXIa inhibition, and to highlight the challenges that this new therapeutic class of anticoagulants will face.