B-lymphocyte stimulator (BLyS) maintains the survival of B cells, and is elevated in serum or locally in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Belimumab (LymphoStat-B) is a fully human IgG1λ monoclonal antibody that binds to soluble human BLyS and inhibits its biological activity. It has been developed for therapy for SLE and the potential treatment of other autoimmune diseases. Belimumab was well tolerated in the treatment of SLE for more than 5 years and of RA for more than 24 weeks. In the pooled analyses of two Phase III trials including 1,684 seropositive SLE patients, a statistically significant improvement was observed for the SLE responder index at week 52 for belimumab 1 mg/kg and 10 mg/kg as compared with placebo (46% vs 39%, P = 0.006; 51% vs 39%, P<0.0001, respectively). It modestly reduced the signs and symptoms of RA, most notably in subgroups such as patients with high disease activity, positive rheumatoid factor, and no prior anti-tumor necrosis factor (TNF) treatment. Belimumab has been approved by the US Food and Drug Administration for the treatment of adult patients with active and seropositive SLE who are receiving standard therapy, but its place in the treatment of RA and other autoimmune diseases remains uncertain. Drug Dev Res 72:623–633, 2011. © 2011 Wiley Periodicals, Inc.