Experimental autoimmune encephalomyelitis (EAE) is a T-cell-mediated demyelinating disease of the central nervous system that has been used as an animal model for multiple sclerosis (MS). Based on the exciting results in EAE, a number of novel immunotherapies employing biotechnological products, rather than conventional immunosuppressants, are being developed for the treatment of MS. In this review, we delineate the rationale for monoclonal antibody (MAb) therapy in EAE and MS and summarize the various levels at which immune intervention was performed. For each approach, we discuss the role of MAbs at the level of lymphocyte and cytokine networks, chemokines, and adhesion molecules or their receptors.