Multiple mechanisms have evolved to maintain tolerance among CD8(+) T cells to innocuous antigens that arise in cutaneous and mucosal tissues. In the thymus, medullary thymic epithelial cells directly present peripheral tissue antigens (PTAs) and incite the deletion of self-reactive thymocytes. Cross-presentation of PTAs by functionally immature, CD8alpha(+) dendritic cells can lead to the deletion of self-reactive CD8(+) T cells in secondary lymphoid organs. A third mechanism of deletional tolerance has recently been uncovered in which lymph node-resident stromal cells of non-hematopoietic origin present endogenously expressed PTAs to circulating CD8(+) T cells. Emerging data suggest that lymph node stroma is a unique niche for controlling self-reactive T cells.