Immunosuppressive therapy has been used to treat multiple sclerosis (MS) for over 30 years based on the hypothesis that MS is a T cell-mediated autoimmune disease. The most commonly used immunosuppressive agents in MS are azathioprine, cyclophosphamide, methotrexate, and mitoxantrone. Since the interferons and glatiramer acetate have become widely used in MS, immunosuppressive agents have found a role given as combination therapy or as monotherapy in instances where the interferons and glatiramer acetate are not effective in controlling the disease. Like the interferons and glatiramer acetate, immunosuppressive drugs are most efficacious in stages of MS that have an inflammatory component as evidenced by relapses and/or gadolinium-enhancing lesions on MRI or in patients in earlier stages of disease where inflammation predominates over degenerative processes in the CNS. There is no evidence of efficacy in primary progressive MS or later stages of secondary progressive MS. In our studies of cyclophosphamide, we have found that although it is a general immunosuppressant that affects both T cell and B cell functions, cyclophosphamide has selective immune effects in MS by suppressing IL-12- and Th1-type responses and enhancing Th2/Th3 responses (IL-4, IL-10, TGF-beta; eosinophils in peripheral blood). Cyclophosphamide and mitoxantrone are the most common immunosuppressive drugs used in patients with rapidly worsening MS whose disease is not controlled by beta-interferon or glatiramer acetate.