The orbital tissues may form a unique immunological environment, as evidenced by autoimmune disorders that specifically target orbital tissues, particularly myasthenia gravis (MG) and Graves' ophthalmopathy (GO). The reasons for the preferential susceptibility are likely to be multiple, based on the interplay of molecular and physiological properties of extraocular muscles (EOM), the unique requirements of the ocular motor system, and the specific autoimmune pathology. Of general importance, even a minor loss of EOM force generation will sufficiently misalign the visual axes to produce dramatic symptoms, and proprioceptive feedback is limited to overcome such a deficit. Particular to MG, EOM synapses appear susceptible to neuromuscular blockade, the autoimmune pathology differs between ocular and generalized MG patients, and the influence of complement regulatory factors may be less prominent in preventing damage at EOM neuromuscular junctions. GO pathogenesis is poorly understood, but shared epitopes of orbital fibroblasts, EOM, and thyroid could lead to specific autoimmune targeting of these tissues. The differential response of orbital fibroblasts to cytokines may be a key factor in disease development. Greater appreciation of the immunologic environment of orbital tissues may lead to therapies specifically designed for orbital autoimmune diseases.