Autoimmune Addison's disease (AAD) represents 70-90% of all cases of primary adrenal insufficiency (PAI) in western countries and Japan. The adrenal autoimmune process is made evident by the appearance of autoantibodies, directed against steroid-21-hydroxylase (21OHAb), the gold marker to identify AAD in patients with clinical and biochemical signs of adrenal insufficiency. 21OHAb have no major pathogenic role, and the disease is thought to be caused by a cell-mediated immune process. In 21OHAb-negative patients, adrenal imaging and very long-chain fatty acids determination should be performed to exclude other causes of PAI such as posttuberculosis Addison's disease or X-linked adrenoleukodystrophy. AAD is a major component of autoimmune polyendocrine syndrome (APS) type 1 and type 2. Isolated AAD and APS2-related AAD are strongly associated with HLA-DRB1 (star)0301 DQA1 (star)0501- DQB1 (star)0201 (DR3-DQ2) and DRB1 (star)04-DQA1 (star)0301 DQB1 (star)0302 (DR4-DQ8). HLA- DRB1 (star)0403 is strongly protective for the development of AAD. Other genetic factors that contribute to the risk of AAD include MICA5.1, and the polymorphisms of the CTLA-4, PTPN22, and MHC2TA genes. Around two-thirds of AAD subjects show clinical or biochemical signs of other autoimmune diseases, the most common being thyroid autoimmune diseases, type 1 diabetes mellitus, and primary ovarian insufficiency. Presence of 21OHAb in subjects with no clinical signs of adrenal insufficiency and with normal basal cortisol levels identifies the so-called subclinical AAD. In subjects with subclinical AAD, a stimulation test with 1 mu g of synthetic ACTH should be performed to discriminate between an early and potentially reversible adrenal dysfunction and a progressive form of the disease.