Using three reference disease models ‐ insulin‐dependent diabetes mellitus (IDDM) as a prototype of T‐cell mediated organ‐specific autoimmune disease, myasthenia gravis (MG) as a prototype of auto and‐body‐inediated organ‐specific autoimmune disease and systemic lupus erythematosus (SLE) as a prototype of non‐organ‐specific autoimmune disease ‐ we have reached several conclusions: 1) All three diseases are associated with the presence of multiple autoantibodies and/or autoreactive T cells that recognize a large number of antigenic molecules. The apparent predominant role of certain antibodies in sotne diseases could relate to their functional properties stich as acetylcholine receptor (AChR) blockade for anti‐AChR autoantibodies in MG or anti‐dsDNA in SLE, 2) Major target antigens are clustered in the target cell affected by organ‐specific autoimmune diseases: β cells in IDDM, striated‐muscle cells in MG, or apopiotic cells in the case of SLE. 3) Antibodies and T cells recognize multiple epitopes in these molecules, 4) The most evident explanation for the observed clustering and diversity is autoantigen spreading. Spreading probably involves T cells secreting proinflammatory cytokines but also possibly antibodies as in the case of nucleosome autoantibodies in SLE. 5) The counterpart of antigen spreading is bystander suppression in which regulatory cytokines deviate the immune response towards a protective response, 6) The mechanisms underlying the initiation of the autoimmune response and antigen spreading are still undetermined. They could imply a direct abnormality of the target cell in the case of organ‐specific autoimmune diseases (e.g. infection with a virus showing a selective tropism for the target cell in organ‐specific autoimmune diseases, or loss of physiological regulation of major histocompatibility complex molecule expression) or could be consequence of a ubiquitous cell abnormality such as increased apoptosis in SLE. The respective roles of genetic and environmental factors in these triggering events remain to be determined.