Recent evidence has provided renewed insight into the role of B cells in the pathophysiology of rheumatoid arthritis (RA). The B cell surface antigen CD20 has been identified as an appropriate therapeutic target in the treatment of a number of immune-mediated conditions, including RA. Binding to CD20 results in depletion of B cells, with an associated improvement in symptoms, while leaving stem and plasma cells - which are devoid of this marker - unaffected. In a randomized double-blind controlled trial in patients with severe active RA who had had an inadequate response to disease modifying antirheumatic drugs (DMARD), a single short course of rituximab, an anti-CD20 chimeric monoclonal antibody, resulted in profound, long-lasting selective peripheral depletion of CD20+ B cells without compromising immunoglobulin levels, as well as significant and clinically meaningful improvements in symptoms of RA for up to 48 weeks without further treatment with rituximab. Rituximab added to existing methotrexate treatment was particularly effective and well tolerated, and provided the basis for further exploration of this promising alternative treatment approach in RA.