N UMEROUS cytotoxic drugs are available for the treatment of severe forms of rheumatic diseases-’ Biologic effects of alkylating agents were first reported in 1887,4 and over the years, these agents have been used extensively in the treatment of neoplastic disease.5.6 Intravenous nitrogen mustard, in 195 1, was reported as clinically effective in the management of two patients with rheumatoid arthritis (RA).’ It is only during the past 20 years that the use of alkylating agents has increased dramatically in the management of rheumatic diseases. Chlorambucil and cyclophosphamide (CP) are the two alkylating agents currently used most often in the management of rhematic disease. Cyclophosphamide, a bifunctionally substituted nitrogen mustard compound, was synthesized in 1958.’ The first major report, albeit uncontrolled, suggesting the benefit of CP for treatment of RA appeared in 1968.9 Since then, numerous controlled and uncontrolled studies have been reported which variably support the use of CP for treatment of a number of rheumatic diseases. These diseases include RA,“” systemic lupus erythematosus, (SLE)12,13 and numerous systemic vasculidites2 The purpose of this review is to summarize the clinical pharmacology and toxicology of CP, with special emphasis on its use in rheumatic diseases.