T cells develop in the thymus where stromal cells provide a unique microenvironment that promotes their development and selection so that naïve T cells exiting to peripheral tissues are purged of reactivity to “Self” specificities but poised to respond to injurious “Non-Self” antigens. Thymic epithelial cells (TECs) constitute an essential component of that environment as they have the unqiue capacity for the promiscuous expression of transcripts that encode proteins which are normally only detected in differentiated organs residing in the periphery (a.k.a. tissue restricted self antigens, TRA). The molecular regulation of TEC development and the cell’s competence for promiscuous gene expression of TRA will be discussed.