Unraveling the mechanisms underlying autoimmune disease remains a difficult challenge. Recent lessons learned from the study of AIRE (autoimmune regulator), the gene responsible for the rare monogenic human syndrome APS-1, highlight the power of genetics to reveal disease pathogenesis. With the discovery of AIRE, central tolerance has re-emerged as a crucial check against autoimmunity. Aire-mediated regulation of diverse self-antigens in the thymus serves as a paradigm for the importance of promiscuous gene expression in the prevention of autoimmune disease. Recent characterization of Aire-targeted antigens continues to bear this out. Here, we review the current progress surrounding the role of Aire in central tolerance from a molecular, genetic and developmental basis.