Systemic lupus erythematosus (SLE) is a representative systemic autoimmune disease characterized by multi-organ manifestation. Although the etiology of the disease remains unclear, the activation of autoreactive T cells and production of antibodies by B cells are mainly involved in the pathological processes of the disease. B cell depletion therapy using anti-CD20 antibody rituximab has shown a rapid onset of effect and prolonged efficacy in refractory SLE, emerging as a promising new agent for the treatment of SLE. We also reported that rituximab is safe for the treatment of active SLE in a domestic pilot study and a multi-center phase I/II clinical trial. In regard to the mechanism underlying the efficacy of rituximab, it has been reported that the drug caused peripheral depletion of memory B cells and plasma cells. We found that rituximab efficiently depleted naive and memory B cells and decreased co-stimulatory molecules on B cells and memory T cells. Recovered B cells in patients in long-term remission were dominated by naïve B cells with an increased ratio of naive T cells, and co-stimulatory molecules remained low. These findings indicate that the reconstitution of the B cell compartment results in the inhibition of T cell activation by memory B cells, which leads to the sustained remission of SLE by rituximab. Although the recent placebo-controlled trials such as EXPLORER with rituximab in SLE did not achieve satisfactory results, other evidence continues to be published in support of the notion that B cell depletion could be useful for refractory SLE. In addition, other B-cell targeted therapies, such as CD22 and agents that interrupt B-T-cell interaction, including belimumab, also have potential of the therapeutic application.