A clear understanding of the events surrounding the selection of autoreactive T cells in the thymus and their regulation in the periphery has eluded immunologists for years. However, recent work examining the expression of tissue-specific antigens in the thymus and the biochemistry of disease associated MHC alleles has provided important clues into the generation of the autoreactive T cell repertoire in the thymus. In addition, recent studies focusing on the role of immunoregulatory cytokines and cross-reactive peptide ligands has provided information regarding both the regulation and activation of autoreactive cells in the periphery. An improved understanding of the selection and regulation of autoreactive T cells will undoubtedly aid in the development of strategies for treating autoimmune disease.