Autoantibodies are a hallmark of systemic rheumatic diseases, organ-specific autoimmune diseases and paraneoplastic syndromes. Cell biologists have used autoantibodies as probes to define the structure and function of novel macromolecules and to determine the chromosomal location of their respective genes. The observation that many autoantibodies appear before the clinical expression of disease suggests that they are not epiphenomena. Some autoantibodies are disease-specific markers and are in aid to establishing a diagnosis. Although it has been difficult to link autoantibodies to pathogenesis, they can be used to predict disease progression and outcome. For example, autoantibodies directed against topoisomerase are associated with progression of scleroderma to diffuse skin involvement and severe systemic disease, whereas antibodies to centromere proteins predict a more slowly progressive disease and development of a limited variant of scleroderma. Certain models of autoantibody production hold promise of a clearer understanding of the mechanisms that underlie autoimmunity. Drugs such as procainamide and hydralazine induce the production of chromatin autoantibodies. Exposure to heavy metals (e.g., mercury) is also linked to the development of autoantibodies. The data provide evidence that the autoimmune response is driven by autoantigens, which are multimolecular complexes involved in essential cellular functions.