Aire (autoimmune regulator), the gene responsible for the clinical disorder autoimmune polyendocrinopathy syndrome type I, has recently been identified as an important mediator of central tolerance. Aire upregulates the transcription of certain organ-specific self-antigens in medullary thymic epithelial cells, and has a role in the negative selection of organ-specific thymocytes. However, the molecular mechanisms by which Aire functions in these processes are still not well understood. Structural characteristics and biochemical data suggest that Aire might have a direct role in nuclear transcription and that it can function as an ubiquitin ligase. Although these molecular details await further characterization, the association of Aire with the prevention of autoimmunity highlights the importance of thymic mechanisms in the maintenance of tolerance.