The thyroid-stimulating hormone receptor (TSHR) has a central role in thyrocyte function and is also one of the major autoantigens for the autoimmune thyroid diseases. We review the post-translational processing, multimerization, and intramolecular cleavage of TSHR, all of which may modulate its signal transduction. The recent characterization of monoclonal antibodies to the TSHR, including stimulating, blocking, and neutral antibodies, have also revealed unique biologic insights into receptor activation and the variety of these TSHR antibodies may help explain the multiple clinical phenotypes seen in autoimmune thyroid diseases. Knowledge of the structure/function relationship of the TSHR is beginning to provide a greater understanding of thyroid physiology and thyroid autoimmunity.