Intravenous cyclophosphamide (CYC) has been the standard of care to induce remission of severe and active lupus nephritis for more than 20 years. Potential side effects are significant, and failure to achieve remission is still high. Mycophenolate mofetil (MMF) has emerged as a potential alternative to CYC, with an improved safety profile thus far. Results of two mayor randomized controlled trials in adults indicate no evidence of inferiority in patients treated with MMF, less adverse events, and higher rate of complete remission. Experience in the pediatric population is very limited. Thus far, the efficacy, toxicity, and tolerability record of MMF in adults makes it an acceptable alternative to CYC in the induction phase of treatment. Early treatment is desired. Several questions remain: the optimal dose and length of induction with MMF are unknown, the effect of MMF in severe cases of lupus nephritis with renal failure at presentation is unknown, and the compliance with long-term oral treatment in the adolescent population is certainly unknown. In this review, intravenous (IV) CYC induction in the sickest patients (renal failure at presentation) is considered and/or when compliance with oral treatment cannot be established. Also, MMF induction in reliable patients with mostly preserved renal function is considered. Most likely, MMF will serve as a therapeutic bridge between the previously well-known, broad-spectrum immunosuppressive drugs and the new, targeted biological agents.