Autoimmunity to thyroid peroxidase (TPO), manifest as high affinity IgG class autoantibodies, is the common denominator of human thyroid autoimmunity, encompassing patients with overt hyper- or hypothyroidism as well as euthyroid individuals with subclinical disease. The identification and cloning of TPO (the "thyroid microsomal antigen") provided the critical tool for analyzing B and T cell reactivity to this major thyroid autoantigen. In particular, the availability of immunoreactive TPO permitted the isolation of essentially the entire repertoire of human monoclonal antibodies, a feat unparalled in an organ-specific autoimmune disease. These recombinant autoantibodies (expressed as Fab) provide insight into the genes encoding their H and L chains as well as the conformational epitopes on TPO with which serum autoantibodies interact. Analyses of TPO autoantibody epitopic "fingerprints" indicate a lack of epitope spreading as well as a genetic basis for their inheritance. Limited data are available for the responses and cytokine profiles of T cells to endogenously processed TPO. Moreover, the role of thyroid cells in initiating the autoimmune response to TPO, and of B cells in expanding and/or modulating the response of sensitized T cells, has yet to be established. Finally, because autoantibody (and likely T cell) responses to TPO parallel those to TSH receptor and thyroglobulin, manipulation of T and B cell responses to TPO may provide the basis for the development of immunospecific therapy for autoimmune thyroid disease in general.