Abstract: The incidence of thrombotic diseases has increased in the past decade, a factor endangering human health. Currently, antithrombotic drugs used in the clinic have side effects such as inducing bleeding. Data from clinical observation indicate that congenital deficiency of factor XI (FXI) gene decreases the incidence of stroke and deep venous thrombosis, without causing spontaneous bleeding. This unique property of FXI makes it a potential new target for antithrombotic drugs development. Many studies have focused on the discovery of novel inhibitors targeting FXI. This review summarizes the research progress in searching for the inhibitors against FXI.