The thymus contributes to the regulation of tolerance and the prevention of autoimmunity at many levels. First, auto-reactive CD4+ and CD8+ T cells are clonally deleted during negative selection in the thymus, establishing central tolerance. The unique expression of the AIRE (autoimmune regulator) gene in medullary thymic epithelial cells results in expression of a broad array of tissue-specific antigens. Thymocytes bearing T-cell receptors that bind to these tissue-specific antigens are clonally deleted. This process removes self-reactive T cells from the repertoire before T cells are exported to the periphery. Second, CD4+CD25 bright regulatory T cells (Treg) develop in parallel with CD4+ and CD8+ effector T cells in the thymus. Unlike T effector cells, Treg fail to be deleted by exposure to tissue antigens during thymic maturation. After export to the periphery, Treg cells play a critical role in the prevention of autoimmunity, suppression of inflammatory responses, and the modulation of T-cell homeostasis. Finally, productive thymopoiesis, in and of itself, may be a factor deterring autoimmunity, The thymus continuously generates stable, resting populations of naive T cells that maintain the numbers and the diversity of the T-cell repertoire. Under conditions of lymphopenia prolonged by inadequate thymopoiesis, compensatory peripheral expansion of T cells occurs to maintain stable T-cell levels. Under circumstances in which the repertoire is limited, Homeostatic proliferation may increase the opportunity for T-cells reactive with self antigens to expand, leading to autoimmune disorders. In all of these respects, the thymus maintains immunologic tolerance to self. Given the importance of the thymus in control of autoimmunity, the gradual age-dependent decline in thymic cytoarchitecture and thymopoietic productivity may, therefore, contribute to the development of auto-reactivity and loss of self-tolerance.