B-cell contributions to human autoimmune disease have recently been emphasized due to the therapeutic benefit of B-cell depleting therapies. B cells are involved in the production of autoantibodies, by CD4+ T-cell activation and control of T-cell function and inflammation, through cytokine production. Although autoantibodies alone may not initiate autoimmune disease, their relationship with the disease course suggests that they are the key mechanisms of disease pathogenesis. In addition to antibody production, B cells are important antigen presenting cells. Maturation of B cells develops through various steps characterized by the expression of several cell surface markers that are potential targets on which B cell-depleting agents can act directly. Rituximab (RTX) has been used off-label in various autoimmune disorders but is approved for clinical use in non-Hodgkins lymphoma (NHL) and RA only. RTX treatment effectively depletes mature and memory CD20+ B cells, but not long-lived plasma cells. The availability of RTX has provided the rationale of its use in GD, since blockade of pathogenic autoantibody generation might bring about Graves hyperthyroidism remission. The effects of RTX in patients with active GO have also been studied. Although, caution is suggested before proposing RTX as a novel therapeutic tool in this disease, data collected show that RTX significantly affect the inflammatory activity and severity of GO. Therefore, we envisage that the optimal strategy to controlling the progression of a disease like GO would be to pursue B-cell depletion shortly after diagnosis and not as an additional therapeutic option when standard immunosuppression has failed.