The immune system has the capability of protection against infectious disease which is accomplished by an enormous repertoire of receptors specifically reactive to foreign antigens, but it is tolerant to self-antigens, establishing biological identity. The ability to discriminate between self and non-self is a central property of the immune system, by using complex network of cellular and molecular mechanisms in order to prevent autoimmunity; this function is called immune tolerance. Thus, the Interaction between immune system and antigens is required for the generation of tolerance and it is critical in different physiological and pathological conditions in order to limit the damage to self tissues. Since Medawar description, who showed that the tolerance is an acquired property playing a central role in the homeostasis, several mechanism has been proposed to explain it. It is accepted today that an important group of antigen specific cells called regulatory T cell, both natural and induced, are critical as a unifying mechanism to maintain self-tolerance. These suppressor lymphocyte subpopulations had shown to play an important role not only by controlling autoimmune disease but also in the pathogenesis of many chronic infectious diseases, either manipulated by the microorganism to escape from the immune system, or induced by the host to reduce inflammatory damage. This review has the intention of updating about modern concepts in immune tolerance mechanisms, with special emphasis played by Treg cell in the tolerance which is unquestionable induced during the course of chronic infections diseases.