Autoimmune T and B cell responses to CNS antigen(s) are thought to drive the pathogenesis of multiple sclerosis (MS), and thus are logical targets for therapy. Indeed, several immunomodulatory agents, including IFN-β1b, IFN-β1a, glatiramer acetate, and mitoxantrone, have had beneficial clinical effects in different forms of MS. However, because the available treatments are only partially effective, MS therapy needs to be further improved. Selective (antigen-specific) immunotherapies are especially appealing because in theory they combine maximal efficacy with minimal side effects. Indeed, several innovative immunotherapies have been successfully applied in experimental autoimmune encephalomyelitis. For example, autoreactive T cells can be selectively targeted by means of antigen, T cell receptor, or activation markers. However, experimental autoimmune encephalomyelitis is far from being a perfect approximation of MS because MS is more heterogeneous and the target antigen(s) is (are) not known. Further advances in MS therapy will depend on our growing understanding of the pathogenesis of this still incurable disease.