Cyclophosphamide is employed in autoimmune neuropathies, and vasculidities such as Wegener's granulomatosis and polyarteritis nodosa. Mycophenolate mofetil (Cellcept) is a potent immunosuppressant and has been used increasingly in post-transplant patients because it is considered less toxic than azathioprine and cyclophosphamide. Methotrexate is a general immunosuppressant that acts primarily by inhibition of dihydrofolate reductase. Azathioprine (Imuran) is a purine analog that is metabolized to 6-mercaptopurine and thioinosine acid, which compete with DNA nucleotides, causing immunosuppression. This chapter lists randomized trials of immunosuppressives in multiple sclerosis (MS). In the right patient, cyclophosphamide has been demonstrated effective, while work with methotrexate and mycophenolate mofetil has been less conclusive. Azathioprine also is likely to have a favorable effect on MS, and is relatively safe. Recent novel uses of immunosuppressives in active patients, or new disease populations have broadened the possible uses of these drugs.