Autoimmune Addison’s disease (AAD) is an endocrine disease resulting from the immune system’s destruction of hormone producing cells in the adrenal cortex. Diagnosis is frequently first established after a life-threatening adrenal crisis, often resulting in untimely fatalities. The disease is rare, more common in women than in men, and also affects children. AAD very frequently occurs with other autoimmune diseases, such as type 1 diabetes mellitus, autoimmune thyroid disease and/or premature ovarian failure. Based on a European network of patient registry and biobanks, a translational approach using genetics, immunology, clinical management, and epidemiology, the project aims to unravel the pathogenesis and natural course of AAD, ultimately to improve diagnosis and treatment as well as to offer strategies for disease prevention. The consortium capitalises on the joint cutting edge expertise of leading European investigators covering all these fields. Exploiting these resources, we will describe the natural course of the disease with focus on factors limiting quality of life, and identify and characterise the disease-causing genes, using the corresponding disease in a spontaneous dog model and a gene targeted mouse model. In parallel, the cellular and molecular mechanisms of autoimmunity directed at the adrenal cortex will be unravelled both in humans with ADD and in the genetic mouse model. Together, these efforts will increase our still incomplete understanding of pathogenic pathways operational in AAD and pave the way for new therapies of this debilitating disorder. Moreover, clinical studies will be performed to evaluate more physiological and personalised treatment with cortisol also aimed at prevention. As an autoimmune model disease the results of the project will not only lead to the development of novel diagnostic and therapeutic interventions for Addison patients, but also increase our understanding of the pathogenesis of autoimmune diseases in general.