More closely analogous to the use of combination therapies in multiple sclerosis (MS) is the use of combination therapies in autoimmune diseases such as rheumatoid arthritis. In the case of MS, drugs could be directed at different therapeutic domains such as tissue destruction and tissue repair. Currently, natalizumab is approved only as a monotherapy. This is due to concern over combined toxicity because of the two cases of progressive multifocal leukoencephalopathy (PML) that occurred in patients enrolled in the combination arm of the SENTINEL trial. Perhaps the most frequently used combination therapy approach utilized in clinical practice for patients with relapsing-remitting MS and continued disease activity while on platform therapy is the ad hoc addition of periodic courses of corticosteroids, most often intravenous methylprednisolone. This chapter discusses cytotoxic therapies and combination trials with other immunomodulating agents such as daclizumab, terilunomide and statins.