During the past two decades, the immunosuppressive drugs azathioprine and cyclophosphamide have been widely used in the treatment of patients with lupus nephritis. Their toxicities are well known and are mostly dose- and time-dependent. Complications that arise from these therapies stem from their immunosuppressive (susceptibility for infection) or pharmacologic (hemorrhagic cystitis, bladder cancer, and fibrosis from the alkylating agents) effects, or both. Uncontrolled studies reporting good results in treating patients with various combinations of corticosteroids and azathioprine and, especially, cyclophosphamide cannot be conclusively confirmed by the few controlled clinical trials that are available for review. Part of the problem of inconclusiveness has to do with timing treatment to different phases of the disease and the vast heterogeneity of lupus nephritis. Although these immunosuppressive agents may have favorable effects on the overall activity of systemic lupus erythematosus, their long-term effects per se on renal disease are in question and could be attributed to lower prednisone dosage and better medical management of hypertension, hyperlipidemia, infection, and other metabolic consequences of the disease.