T-lymphocytes recognize antigen in a trimolecular complex: The T-cell receptor binds to a processed fragment of antigen that itself is bound to a major histocompatibility complex (MHC) molecule on the surface of an antigen-presenting cell. The trimolecular complex controls antigen-specific T-cell activation in normal and abnormal immune reactions. Recent progress in myasthenia gravis (MG) and experimental autoimmune encephalomyelitis (EAE) exemplifies this, leading to the following conclusions: (1) Autoimmune T cells may act by interfering with immunoregulation (as in MG) or by directly mediating autoimmune damage (as in EAE), or both. (2) In both diseases, the autoimmune T cells are clonally heterogeneous but recognize only a limited number of epitopes on the autoantigen (acetylcholine receptor in MG; myelin basic protein in EAE). Many of these epitopes can be defined as short peptide fragments of antigen, bound to a particular type of MHC molecule. (3) The MHC determines which peptides are recognized by autoimmune T cells in a given patient or inbred animal strain. (4) The discovery of the limited repertoire of autoimmune T cells has allowed considerable progress in the immunotherapy of EAE, using either monoclonal antibodies or cytotoxic T cells directed against clonotypic determinants on the autoaggressive T cells. (5) One obstacle to this approach in human disease is the polymorphism of the MHC in the species and the commensurate heterogeneity of autoimmune T cells.