Intravenous cyclophosphamide therapy for autoimmune disease continues to be the subject of many clinical trials, which in general have strongly supported its use in lupus nephritis but have failed to demonstrate efficacy in severe vasculitis or severe Wegener's granulomatosis. A particularly difficult issue is the use of this medical therapy in neurologic disease. Uncertainty as to the patholophysiologic processes leading to development of neurologic symptoms, particularly in patients with systemic lupus, and difficulty in following response to clinical trials objectively have been associated with a relative lack of information about the efficacy of cyclophosphamide therapy. This review will focus on treatment of neurologic lupus and review the use of cyclophosphamide in multiple sclerosis as well.