Non-surgical treatments for moderate to severe and active Graves' orbitopathy (systemic glucocorticoids with or without orbital radiotherapy) have limited effects on the underlying autoimmune process causing the disease. Although the clinical responses to treatment are often good, at least one third of patients with Graves' orbitopathy are eventually dissatisfied with the treatment outcome. Progress in our understanding of the autoimmune basis of Graves' orbitopathy (although still incomplete) made it possible, similar to other autoimmune disorders, to envision the use of novel immunomodulating drugs. Among the currently available biologic agents, the CD20+ B cell-depleting agent, rituximab, and tumor necrosis factor-alpha inhibitors are presently the drugs that have the best chance of being employed in the future for the treatment of Graves' orbitopathy. However, randomized, controlled clinical trials to support their use are warranted.