The TSH receptor (TSHr) is the autoantigen responsible for the hyperthyroidism of Graves' disease. Recent studies suggest that this receptor may also be an autoimmune target in Graves' ophthalmopathy (GO) and pretibial dermopathy (PTD). Its involvement in the pathogenesis of these conditions would help to explain the close clinical associations between hyperthyroidism, GO and PTD. TSHr has been shown to be present in normal orbital and dermal tissues and evidence supports the conviction that expression may be increased in tissues involved in GO and PTD. In the setting of Graves' disease, the expression of this antigen in connective tissues throughout the body may lead to systemic, subclinical connective tissue inflammation. Given this background, local or environmental factors such as circulating or local cytokines, gravitational dependency, anatomic constraint of the bony orbit, or trauma, may augment clinical disease involvement within the orbit and pretibial skin. Alternately, locally enhanced expression of this protein at the sites of clinical disease may not be directly involved in pathogenesis, but could be secondary to the ongoing process, and nonetheless important in disease progression.