Several trials of new immunologic agents in systemic lupus erythematosus (SLE) have recently been undertaken. Rituximab, a chimeric antibody directed against CD20 on B lymphocytes, has emerged as a promising therapy. Based upon preliminary data, clinical efficacy of rituximab has been documented in both pediatric and adult-onset SLE patients. The specific manifestations reported to be beneficially affected include lupus nephritis, arthralgia/arthritis, serositis, cutaneous vasculitis, mucositis, rashes, fatigue and neurologic symptoms. Although rituximab's mechanisms of action are incompletely understood, the effects of rituximab are likely mediated by antibody-dependent cell-mediated cytotoxicity and the induction of apoptosis. The resultant repopulation of B cells, alteration of abnormal B cell homeostasis and down-regulation of co-stimulatory molecules on both B and T cells all likely contribute to clinical efficacy. Good tolerability of rituximab is reported with rare serious side effects. The positive response to rituximab verifies a central role for B cells in SLE. This article highlights the clinical experience of rituximab therapy in both pediatric and adult-onset SLE. These data suggest a promising role for rituximab in the treatment of SLE. Further controlled trials and long-term outcome studies are imperative to further define its clinical application and to improve the care of patients.