Medical management of overt and active Graves’ orbi-topathy is frequently unsatisfactory, both for the patientand the physician [1]. Systemic glucocorticoids, moreefficaciously given intravenously [2], represent the first-line treatment [3, 4], but many patients require a secondcourse of steroids, associated with orbital radiotherapy orcyclosporine, to inactivate the disease [5]. And, eventually,some kind of rehabilitative surgery (orbital decompression,squint surgery, eyelid surgery) is needed in many patientswhen GO is inactive to correct residual invalidating man-ifestations, such as exophthalmos, strabismus/diplopia,eyelid retraction [3].Reasons why glucocorticoids are not always effectiveare not fully understood. They include selection of patientswith long-lasting GO, prevalence of proptosis with limitedinflammatory changes, long-standing eye muscle dysfunc-tion associated with fibrotic changes, smoking habits,mutations in the glucocorticoid receptor causing adecreased sensitivity to the drug. Most importantly, glu-cocorticoids, despite immunosuppressive actions, aremainly anti-inflammatory drugs and cannot be really con-sidered pathogenic drugs. Autoimmune pathogenesis ofGO is extremely complex, involving autoreactive T lym-phocytes, B-lymphocytes, the TSH receptor, the IGF-1receptor, secretion of a number of cytokines automain-taining the reactions occurring in the orbit. Studies areongoing to completely unveil the multiple steps of thecascade of events eventually causing remodeling of theorbital tissue, with an increase in the fibroadipose tissueand swelling of the extraocular muscles [6]. These studiesare essential to define the target of novel (‘‘pathogenic’’)treatments (T-cells? B-cells? Cytokines?). Among clinicalstudies based on better understanding of orbital patho-physiological processes, promising, although preliminary,results come from the evaluation of the CD20? depletingagent, rituximab [7] or some anti-TNFa agents [8]. Inpatients with mild GO, selenium administration for6 months prevented the progression to more severe formsof eye disease [9]. Expansion of the orbital adipose tissue isundoubtedly a key feature of GO under most circum-stances. In this issue of Endocrine, Zhang et al. [10]evaluated the effects of thalidomide on preadipocytes(3T3-L1 preadipocytes) and orbital fibroblasts from fewpatients with GO. This agent was initially used as an oralsedative hypnotic, but it is now used in the management ofseveral autoimmune disorders in view of its anti-inflam-matory and anti-angiogenic features. In Zhang et al.’sstudy, thalidomide dose-dependently inhibited adipogene-sis of 3T3-L1 preadipocytes; this was associated with adecreased expression of PPARc and the TSH receptor [10].These inhibitory effects were also observed on the differ-entiation of preadipocyte fibroblasts from GO orbital tissueinto adipocytes, in which the expression of TNFa and IL-6was also reduced by thalidomide [10]. The main limitationof this ex vivo study is the small size, because tissue fromonly three patients with GO was utilized. However, itseems reasonable to try and reproduce these preliminaryresults in larger studies before envisioning or advocating itspossible use in clinical practice in patients with GO.Pathogenesis of GO is so complex and implies the partic-ipation of so many actors that it is presently hard to believethat a single drug can cure or control the disease. It ishowever worth keep on trying.