Autoimmune polyendocrine syndrome type-1 clinically manifests as the triad of hypoparathyroidism, primary adrenocortical insufficiency, and chronic mucocutaneous candidiasis. Mutations in the gene that encodes the autoimmune regulator protein, AIRE, have been identified as the cause of the autoimmune polyendocrine syndrome type-1. The loss of immunologic tolerance to tissue-restricted antigens consequent to an absence of AIRE expression in the thymus results in the thymic export of autoreactive T cells that initiate autoimmunity. In this article, we discuss the role of AIRE in autoimmune polyendocrine syndrome type-1 and identify issues that still need to be addressed to fully understand the molecular pathophysiology of this complex syndrome.