Although the cause of multiple sclerosis (MS) has remained obscure, many findings support an autoimmune pathogenesis on the background of a complex interaction between multiple genes and environmental factors. Accordingly, targeting the immune system has been a rational approach for the treatment of MS. The development of disease-modifying immunomodulatory drugs with partial efficacy, coupled with advances in understanding the pathophysiology and pathology of MS, has provided momentum to explore more specific and hopefully more effective immune-based therapeutic strategies. With increased knowledge and appreciation of the contribution of neurodegenerative processes to disease pathology, the therapeutic challenges, however, have become even more formidable. Future treatments will likely need both to target inflammation and to focus on promotion of neuroprotection and repair. In this review, we discuss the most promising therapeutic approaches for MS currently in the pipeline.