The recent advances in our understanding of immunology have greatly improved our knowledge about the natural history of autoimmune diseases and, in particular, of autoimmune Addison's disease (Autoimmune AD). Autoimmune AD is a chronic disorder with a long preclinical period marked by the presence of adrenal cortex autoantibodies (ACAs). In this chapter the main data on this will be analyzed. The populations with the highest risk of Autoimmune AD are first relatives of patients with AAD and patients with autoimmune diseases, particularly those with chronic hypoparathyroidism or with premature ovarian failure. The best markers to identify the subjects at risk are ACAs detected by the immunofluorescence test on human or animal tissues, or 21-hydroxylase autoantibodies (21-OHAbs) detected by radioimmunoassay (RIA). The evaluation of adrenal cortex function in these individuals includes the basal determination of adrenocorticotropic hormone (ACTH), cortisol, aldosterone, plasma renin activity and cortisol after intravenous stimulation with synthetic ACTH. The multivariate analysis of the main factors (genetics, age, gender, titers of antibodies, pre-existing disease, status of the adrenal function) revealed that the risk of future AAD depends only on the presence of high antibody titers, chronic hypoparathyroidism or chronic candidiasis and adrenal dysfunction. On the basis of these parameters the risk of future Autoimmune AD can be calculated with an equation model. Patients with different risk scores need to be monitored at different time intervals, and those at high risk need to be strictly monitored and are the ideal subjects for future prevention trials.