Orbital fibroblasts exhibit a unique phenotype including exaggerated responses to proinflammatory cytokines. We hypothesize that the unusual susceptability of these fibroblasts to molecular cues underlies the involvement of the orbit in Graves' ophthalmopathy. A number of attributes of orbital fibroblasts are reviewed in this article. In addition, we have found IgG circulating in patients with Graves' disease that binds and activates the insulin-like growth factor-1 receptor displayed on fibroblasts from many anatomic regions. Activation of this receptor leads to the expression of T-cell chemoattractants. Thus, fibroblast activation, and the resulting T-cell trafficking to connective tissue in Graves' disease may be systemic. The consequences of lymphocyte-derived cytokine action may differ vastly in the orbit and other tissues manifesting clinically obvious disease.