The convergence of studies in the clinical and basic sciences has resulted in the definitive identification of many intracellular antigens which are the targets of autoantibodies in patients with systemic lupus erythematosus, scleroderma, dermatomyositis/polymyositis, Sjogren's syndrome, mixed connective tissue disease, and drug-induced autoimmunity. Some of this new knowledge includes the identification of the Sm and RNP antigens as ribonucleoprotein particles involved in splicing of precursor messenger RNA, Scl-70 as DNA topoisomerase I, proliferating cell nuclear antigen as auxiliary protein of DNA polymerase delta, and certain antigens in myositis as aminoacyl transfer RNA synthetases. This information confirms, at a molecular level, the presence of specific profiles of autoimmune responses so that autoantibodies can be used in clinical medicine as diagnostically useful immune markers. In addition the data give compelling reasons to consider that certain autoimmune diseases are antigen-driven. Many auto-antibodies have the interesting feature of recognizing epitopes on the antigens which are active or functional sites of the molecule. It is suggested that the data provide clues to the nature of the intracellular particle initiating the immune response and may help to elucidate some of the early mechanisms of the autoimmune process.