Considerable interest in the efficacy of rituximab (a monoclonal CD20 antibody) in patients with systemic lupus erythematosus (SLE) has been generated due to its unique mode of action, culminating in a series of randomized and open trials, and case reports. However, this use is off-license and two significant RCTs have reported negative findings, reopening the debate on clinical benefit. This review of the available data suggests that rituximab induces B-cell depletion in 95% of patients, and a significant reduction in disease activity is achieved with a relatively good safety profile in patients with SLE.