The autoimmune regulator (AIRE) is a gene where mutations cause the recessively inherited disorder called autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) or autoimmune polyendocrinopathy syndrome type 1 (APS1). Variable combinations of autoimmune endocrine diseases such as Addison's disease, hypoparathyroidism, and type 1 diabetes characterize APECED. The AIRE protein has several domains indicative of a transcriptional regulator. AIRE contains two PHD (plant homeodomain) type zinc fingers, four nuclear receptor binding LXXLL motifs, a putative DNA-binding domain named SAND and, in addition, a highly conserved N-terminal domain similar to the homogenously staining region domain of the Sp100 protein. At the subcellular level, AIRE is expressed in nuclear dots resembling promyelocytic leukemia nuclear bodies, which are associated with several transcriptionally active proteins. AIRE is primarily expressed in thymic medullary epithelial cells and monocyte-dendritic cells in the thymus but also in a rare subset of cells in the lymph nodes, spleen and fetal liver. The disease, caused by mutations in AIRE, its function as a protein involved in transcription, and its restricted expression in cells important in negative selection, all together suggest that AIRE is a central protein in the maintenance of immune tolerance. In this review of the recent literature we discuss the results of these studies with particular attention on the AIRE expression pattern and its function as a transcriptional regulator, as well as the effects of patient mutations on the molecular characteristics of the protein.