Induction and maintenance of self-tolerance in the developing and mature T cell repertoire is mediated by multiple mechanisms operating both in the thymus ("central tolerance") and in peripheral lymphoid and nonlymphoid organs ("peripheral tolerance"). The thymus is viewed as the prime site of T cell tolerance induction to ubiquitous proteins and abundant blood-borne antigens entering the thymus via the circulation. By contrast, tolerance to self-antigens that are confined to specific tissues has been ascribed to a variety of mechanisms acting on peripheral T cells. Based on the recent finding that intrathymic expression of "tissue-specific" antigens is a common occurrence the prevailing notion that tolerance induction in the thymus applies only to a limited set of "abundant" proteins may have to be revised. Interestingly, this "promiscuous" expression of tissue antigens in the thymus appears to be a unique property of thymic epithelial cells rather than bone marrow derived antigen-presenting cells, implying cell type specific regulation rather than basal leakiness as a mechanism of "promiscuous" gene transcription. We summarize recent experimental evidence supporting this novel concept and discuss implications for autoimmunity.