Immunosuppression is currently the treatment of choice to attenuate the chronic deterioration of tissue function as a result of the effector mechanisms of the immunological response in transplant rejection and autoimmune diseases. However, global immunosuppression greatly increases the risk of acquiring life-threatening infections and is associated with organ toxicity when used long-term. Thus, alternative approaches that inhibit only the unwanted immune responses and preserve general immunity are highly desirable. The receptor/ligand pairs involved in the cross-talk between DC and T cells have been the focus of intense and exciting research during the last decade. The HVEM/LIGHT/BTLA/CD160 costimulatory/coinhibitory pathway has emerged as a potential target for the development of immune therapeutic interventions. Herein, we will summarize and discuss how blockade of the costimulatory HVEM/LIGHT interaction or agonist signaling through the inhibitory BTLA and CD160 receptors could contribute to the control of deleterious immune responses.