ABSTRACTImmune checkpoints are important molecules that regulate the immune response, preventing its overactivation from causing tissue damage and autoimmune diseases. B and T lymphocyte attenuator (BTLA) plays an important role in regulating the activation and suppression of the immune response as part of a bidirectional signaling complex. The BTLA and its ligand herpesvirus entry mediator (HVEM) interaction transmits inhibitory signals that suppress the biological activity of T cells, B cells, and DCs. In addition, BTLA–HVEM can affect the induction of Treg cells, further suggesting its important role in immune regulation. Organ transplantation is the ultimate treatment option for many patients with end‐stage organ failure. Transplant rejection can cause damage to the transplanted organ, which seriously affects the prognosis of patients. Therefore, we would like to explore the potential application value of the BTLA–HVEM interaction to exert an immunosuppressive function and thus attenuate transplant rejection. We first reviewed the structure and function of BTLA and HVEM, then summarized their research progress in organ transplantation, and further explored the directions of potential future applications and the challenges of current BTLA–HVEM applications.