B cells have multiple actions on different phases of an immune reaction, mainly resulting in B and T cell-interaction (help), production of cytokines, regulation of dendritic cells and downregulation of regulatory B cells. The effectiveness of B cell depletion therapy is probably due to blockade of the antigen-presenting function of B cells, occurring very early in the setting of autoimmune reactions. B cells undergo a maturation process from stem cells during which the CD 20 antigen, which is the target of rituximab (RTX), is expressed from the stage of pre-B cells to mature and memory B cells, but not on plasma cells. During the maturation process, the cytokine B cell stimulating factor (BAFF) induces maturation of B cells and expansion of clones to produce plasma cells and eventually antibodies. The effect of RTX in GO is rather rapid, with significant improvement of the disease already 4-6 weeks after the first RTX infusion. Based on the evidence of significant lymphocytic infiltration in the orbits of patients with active GO, it is reasonable to postulate that RTX may cause depletion of B cells and block their antigen-presenting cell mechanism. Since it has been reported that serum BAFF concentrations are elevated in hyperthyroid GD patients and that BAFF is expressed on the thyrocytes of patients with either autoimmune disease or nodular goiter, the hypothesis that belimumab, an anti-BAFF monoclonal antibody, may be effective in patients with active GO his currently being tested in a randomized controlled trial.