Treatment of Graves' orbitopathy (GO) is a major challenge, and the outcome of medical therapy is unsatisfactory in about one-third of cases. Glucocorticoids are the first-line therapy for moderate-to-severe and active GO, more commonly given through the intravenous route. Uncertainty remains as to the best therapeutic approach when the initial glucocorticoid treatment provides an incomplete response or no response. The choice largely depends on personal experience because of the limited evidence in this field. In the author's view, if a first course of glucocorticoids provides a suboptimal response, a second course of intravenous (or oral) glucocorticoids associated with orbital radiotherapy should be given. An alternative might be represented by oral glucocorticoids associated with cyclosporine. The use of biological agents, the most promising being rituximab, is for the time being experimental and warrants support from randomized clinical trials.