Renal involvement in systemic lupus erythematosus is a common complication that significantly worsens morbidity and mortality. Landmark trials conducted by the National Institutes of Health established cyclophosphamide as the mainstay of therapy. Since then, the prognosis of patients with lupus nephritis has markedly improved, and 10-year survival rates now surpass 75%. These superior outcomes have come at the expense of adverse events such as serious infections and gonadal failure in a significant number of patients, and the relapsing nature of the disease continues to pose a problem. For these reasons, new treatment protocols, such as mycophenolate mofetil induction or sequential therapies using azathioprine or mycophenolate mofetil in the maintenance phase, have been developed in recent years with the goal to maintain remission and reduce adverse events. In addition, ongoing research into the pathogenesis of lupus nephritis has confirmed the importance of B and T cell activation, leading to the identification of potential new therapeutic targets. This article discusses established and novel treatment options for patients with severe lupus nephritis corresponding to WHO classes III, IV, and V with III or V with IV.