Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are both chronic autoimmune rheumatic diseases. In the last few years, evolution in the understanding of RA and SLE pathogenesis and underlying molecular mechanisms has resulted in development and availability of novel therapies. In particular, the recent acknowledgement of a more significant role for B cells in the pathogenesis of RA, in contrast to the view that it was predominantly a T cell disorder, provided rationale for trials of B cell depletion therapy with the chimeric anti-CD20 monoclonal antibody rituximab. The efficacy and favourable safety profile of rituximab have resulted in the recent approval by the European Medicines Agency for its usage in patients with RA unresponsive to conventional therapies. The salient features from the pivotal open and randomised controlled trials are reviewed in this chapter. Given the recognition of B cell dysfunction as central to SLE pathogenesis, the use of anti-CD20 antibody therapy for this patient group has also been established. Results of the open trials have been encouraging, particularly in patients not responding to usual therapies, and a randomised controlled trial is underway.