T lymphocytes respond to small peptides in the context of major histocompatibility molecules and a host of other cell-surface proteins on antigen-presenting cells. By design, therefore, T-cell responses are dependent on the efficient and accurate processing of both foreign and self peptides by antigen-presenting cells. This review examines the functions of T cells that may be specific for self peptides processed and presented under less than ideal conditions or outside the normal pathways of antigen processing. Do these T cells survive selection events and remain in the repertoire of normal lymphocytes? Moreover, can these cells become activated and are they important in the pathogenesis of autoimmunity?