Rheumatoid arthritis (RA) is a human systemic autoimmune disease with a prevalence of about 1%. Although an important role for B cells has been demonstrated in animal models of autoimmune, inflammatory arthritis, the importance of B cells in RA has been controversial for decades. The development of therapies targeting B cells may help to resolve this debate. Rituximab, a mouse-human chimeric monoclonal antibody against the B cell-specific antigen CD20, was the first B cell-targeted therapy tested in double-blind, placebo-controlled trials for RA. On the basis of the data from three separate trials, addition of rituximab to methotrexate appears to reduce significantly the signs and symptoms of rheumatoid factor-seropositive RA, as assessed by American College of Rheumatology (ACR) 20, 50 and 70 response criteria, and to be relatively safe. Significant questions about rituximab therapy still need to be addressed, including whether or not treatment with rituximab reduces radiographic progression of joint damage, the safety and efficacy of repeated courses of rituximab, and the long-term effects of rituximab on the immune system. Preliminary data on treatment of RA with belimumab, a fully human monoclonal antibody against B lymphocyte stimulator (a growth and survival factor for B cells) is now available. In a double-blind, placebo-controlled, phase II trial, belimumab was well tolerated and had a significant beneficial effect on the ACR 20 response. Thus, therapies specifically targeting B cells do appear to be effective in the treatment of RA, providing direct evidence that B cells are important in the pathogenesis of RA.