Childhood-onset systemic lupus erythematosus (SLE) is a multisystemic autoimmune disease associated with significant morbidity and mortality with lupus nephritis being a major prognostic factor. Children with SLE tend to have more severe hematologic and renal involvement compared with adults. Although the morbidity and mortality have greatly improved over the last 20 years, recent studies show that there are still associated major risks from under treatment (with resultant severe flares of disease activity) and over treatment (with additional medication adverse effects including risks of severe infection; many of these patients have inherent abnormal complement pathways). Therapies used to treat children with SLE need to be individualized based on multiorgan involvement, severity of disease, history of disease flares, and knowledge of recent relevant clinical, hematologic, and immunologic parameters. These medications need to be the most effective treatments, allowing normal growth, development, fertility, and the avoidance of severe toxicity and future malignancies. Many toxic effects of current medications range from the well described Cushingoid features of corticosteroids to the gastrointestinal adverse effects of mycophenolate mofetil. In vitro studies have shown that rituximab causes B-cell depletion by mechanisms involving antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity, and direct signaling leading to apoptosis. As the adverse effect profile of B-cell depletion with rituximab has been well described in adults and children with oncologic and other autoimmune diseases, initial pilot studies using rituximab in patients with refractory SLE have been carried out according to different protocols. Evidence to date in open studies demonstrates that targeted B-cell depletion therapy can be safe and efficacious as an addition to standard immunosuppressant agents in refractory childhood-onset and adult-onset disease. Although there are positive outcomes in using this therapy, caution is necessary with respect to minimizing the number of doses and treatments given to reduce the incidence of developing human anti-chimeric antibodies. The next phase for the clinical and research community are multicenter randomized controlled trials of rituximab in severe childhood SLE, such as a comparative trial of rituximab versus intravenous cyclophosphamide in patients both at presentation and with exacerbations of disease activity.