Cyclophosphamide remains the 'gold standard' treatment for severe organ threatening systemic lupus erythematosus (SLE), especially renal and central nervous system lupus. Intravenous and oral cyclophosphamide have been compared, retrospectively, with similar two year remission rates of 73% and 90%. In a meta-analysis, intravenous cyclophosphamide with oral prednisone is more effective than oral prednisone alone. The efficacy of cyclophosphamide in lupus nephritis has been proven in multiple clinical trials, but efficacy has to be balanced with toxicity, including infection, gonadal failure, and malignancy. Although the continued use ofcyclophosphamide for renal lupus has been challenged by a recent trial of mycophenolate mofetil, and may be challenged in the future by planned trials of biologics, it continues to be widely used. This review will touch on the traditional intravenous 'pulse' cyclophosphamide regimen, consider its toxicity, and contrast it with newer approaches to cyclophosphamide.