One of the miracles of immunology is tolerance, the ability of the immune system to differentiate self from nonself and leave the former alone. Autoreactive thymocytes (the cells that would otherwise differentiate into mature autoaggressive T cells) are deleted from the emerging immunologic repertoire within the thymus; only a very small proportion of thymocytes survive the thymus--perhaps 2% to 5% emerge to become mature T cells in the periphery, the rest dying to assure tolerance. This apparent wastage somehow works to the benefit of the developing animal and if the process works, all goes well for the maturing immune system. In some autoimmune syndromes, autoreactive thymocytes are not eliminated within the thymus by either clonal deletion or activation-induced cell death; these then emerge to wreak their havoc. However, how does this deletion happen? Recent research from a number of groups has (incredibly!) identified expression of nonthymic, nonlymphoid proteins within the thymus (casting of the "immunologic shadow of self"), and this is under the control of a single protein: AIRE (autoimmune regulator). By allowing autoreactive thymocytes to encounter a broad spectrum of proteins from extrathymic organs, aire allows deletion of these cells and the maintenance of tolerance. The absence of aire leads to autoimmune polyendocrinopathy, proof that aire is the center of an amazing "filtering" system. These and other molecular mechanisms underlying tolerance are explored in this and the next paper in this series.