In autoimmune diseases, autoantibodies may be the actual pathogenetic agents of the disease, the secondary consequences of tissue damage, or the harmless footprints of an etiologic agent. Establishing a pathogenetic role for autoantibodies requires that they meet stringent criteria. It appears that the location of the presumptive target antigen most critically influences the pathogenetic potential of autoantibodies. Autoantibodies directed against cell surface targets, such as hormone receptors, are clearly pathogenetic; those directed against extracellular targets, such as circulating molecules or extracellular matrix, may or may not cause any damage. Those apparently directed against intracellular targets are usually not pathogenetic unless it can be clearly demonstrated (a) that the antigen is released from within the cell so that it can bind onto a cell surface receptor or other extracellular location, such as proteinase 3; (b) that the antigen moves to an aberrant site on the cell surface, such as, perhaps, the small ribonucleoprotein antigen Ro; or (c) that a cross-reactive molecule, the actual target, such as the membrane ribosomal P-like protein, is at an accessible location.