Autoantibodies (AA) are a serological hallmark of most autoimmune diseases. In contrast to genetic markers that show a predisposition for disease development, certain AA serve as diagnostic biomarkers and classification criteria for a number of these conditions. The role of AA is still not clearly understood: some are pathogenic, some disease specific and others serve as predictors of disease outcome, but little is known about those that protect against disease or serve as signatures of the inciting agent of autoimmunity. Because of growing evidence that some AA antedate clinical diagnosis, significant effort is being spent on gathering evidence regarding their value as predictors of disease onset and outcome. Although many studies have shown that specific AA are detected in the pre-clinical phase and are biomarkers of increased risk of developing an autoimmune disease, they are currently not widely used to determine risk or as a pre-clinical screen. Additional prospective and retrospective studies are urgently needed to determine the precise risk of developing autoimmune disease in the presence of various AA. Such studies must be attended by the development of strategies for earlier diagnosis and novel therapeutic interventions of early disease.