The treatment of lupus nephritis has evolved over many decades and cyclophosphamide has become the standard of care for proliferative lupus nephritis. This article describes the development of a protocol that utilises fixed low doses of cyclophosphamide followed sequentially by azathioprine as a maintenance agent, which has stood the test of time. As novel therapies and biologic agents are more widely used, it is likely that cyclophosphamide use will decline. In particular the prolonged high-dose regimen pioneered by the National Institutes of Health studies will no longer be used on account of its toxicity.