Autoimmune thyroid diseases represent the most common autoimmune disorders, yet we have little understanding of the reasons for the breakdown of immune tolerance leading to the development of autoimmunity. It is likely that thyroid peroxidase has a key role in the development of thyroiditis in autoimmune thyroid disease. Recent advances in thyroid peroxidase have been made in understanding the immunodommant serologic determinants implicated in autoimmunity, the potential pathogenicity of its autoantibodies, the protein products of its alternatively spliced forms of mRNA, and its cell biology and intracellular trafficking in polarized cells, such as thyroid cells. Although the detailed tertiary structure is not known, molecular modeling of thyroid peroxidase based on the structure of the homologous mammalian peroxidase, myeloperoxidase has allowed consideration of predicted structures in autoimmunity. These studies are beginning to shed a new light on the role of thyroid peroxidase in a pathogenic role in thyroid autoimmune disease.