Hemophilia, an X-linked genetic bleeding disorder, is caused by the deficiency of coagulation factors VIII (hemophilia A) or IX (hemophilia B). Regular replacement therapy with the missing clotting factor is an effective standard-of-care treatment. However, it comes with a significant fallout of frequent intravenous dosing with poor compliance, the risk of inhibitor development, and a substantial treatment burden. Research has progressed from missing clotting factors and factor VIII mimetics to the most recent rebalancing therapy that suppresses tissue factor pathway inhibitor (TFPI). Thrombin generation is restricted by TFPI, which inhibits the tissue factor-mediated activation of factor VII. This promising therapeutic approach rebalances hemostasis by inhibiting TFPI, a critical regulator of the extrinsic coagulation pathway, thereby increasing thrombin generation. Novel monoclonal antibodies (concizumab and marstacimab) enhance thrombin generation by blocking TFPI to restore hemostasis. Clinical trials have demonstrated good clinical efficacy and safety of these anti-TFPI, besides their convenient subcutaneous administration using pen devices. These innovative therapies have the potential to enhance the quality of life (QoL) of people with hemophilia. This review provides a comprehensive overview of the clinical development, therapeutic potential, challenges, and prospects of anti-TFPI in the management of hemophilia.