The major goal of studies on immunity to Trypanosoma cruzi is the understanding of immunological mechanisms involved in resistance to this protozoan as well as the pathogenesis of Chagas' disease. Different studies have defined CD8+ T lymphocytes, IFN-gamma and macrophages as important elements controlling parasite replication during the acute phase of infection. In contrast, during the chronic stage of the disease parasite-specific antibodies that fix complement and lyse the blood from trypomastigotes are thought to be the main effector molecules responsible for maintaining latent infection. In both acute and chronic infection with T. cruzi CD4+ Th1 lymphocytes appear to be the main cells responsible for induction of protective immunity. The immunological mechanisms involved in the pathogenesis of Chagas' disease are much more controversial. CD8+ lymphocytes are thought to be the main effector cells responsible for cardiac tissue destruction. Although many experiments suggest the involvement of autoimmunity in the pathogenesis of Chagas' disease, recent studies both in mice and humans indicate a positive association of tissue parasitism, inflammation and severity of pathology induced by T. cruzi. Finally, T. cruzi has emerged as an important opportunistic pathogen in patients infected with HIV and presenting low numbers of CD4+ T lymphocytes. These clinical findings indicate the essential requirement of CD4+ T-helper cells in mediating resistance during chronic Chagas' disease; however, the effector mechanisms that control the reactivation of chronic infection in vivo are not completely defined.