Despite the development of new modalities, cyclophosphamide (CYC) remains the preferred initial treatment for severe proliferative lupus nephritis. Controversies continue about the best route, dosage, and duration of CYC treatment. For recalcitrant disease, new immunosuppressive and immunomodulating agents, immunoablative high dose CYC, nucleoside analogues, apheresis, and the biological response modifiers can be considered.