Thrombosis remains one of the leading causes of death in the world. The history of anticoagulation has evolved considerably from non-specific drugs (i.e., heparins and vitamin K antagonists, VKA) to agents that directly target specific coagulation factors (i.e., argatroban, fondaparinux and direct oral anticoagulants, DOAC). Since the last decade, DOAC are widely used in clinical practice because of their ease to use with favorable pharmacological profile and not requiring monitoring, particularly for venous thromboembolism treatment and prevention and stroke prevention in atrial fibrillation. However, despite having a better safety profile than VKA, their bleeding risk is not negligible. Therefore, research is underway to develop new anticoagulant therapies with a better safety profile. One of these news approaches to reduce the risk of bleeding is to target the coagulation in the intrinsic pathway, in particular the contact activation, with the ultimate goal of preventing thrombosis without impairing hemostasis. Based on epidemiological data with patients with inherited factor XI (FXI) deficiency and preclinical studies, FXI emerged as the most promising candidate target separating hemostasis from thrombosis. This review summaries the role of FXI and FXIa in hemostasis, provides evidence of initial success with FXI pathway inhibitors in clinical trials (such as IONIS-FXI_Rx, fesomersen, osocimab, abelacimab, milvexian, asundexian or xisomab 3G3) and highlights the opportunities and challenges for this next generation of anticoagulants.