MS is a chronic inflammatory disease of the central nervous system (CNS). MS is a predominantly CD4+ T cell mediated autoimmune disorder. Recent studies have challenged this existing paradigm by supporting the role of other immune cells and factors (even non-immune) including CNS antigen-driven clonally expanded B cells, autoantibodies, complement and mediators of the innate immune responses in MS lesions. Further expansion of this global CNS dysfunction includes oligodendroglial cell (OGC) loss, attenuated remyelination, axonopathy, and gliosis. The recognition of new "players" directing effector and regulatory functions and further insight into reparative mechanisms occurring at various stages of the disease within a given individual will influence ongoing and future therapeutic trials. The following discussion will encompass evolving concepts in the pathogenesis of MS with a focus on novel immunotherapies. These new approaches reflect targeting of a multifaceted spectrum of immune activity. The immunotherapies will be characterized by their intervening role of specific and/or multiple pathogenic steps including initiation, peripheral activation, molecular co-stimulation and immune effector responses during early, transitional and late phases of disease. Emerging strategies for the enhancement of neuroprotection and reparative mechanisms will also be reviewed. Classification of novel approaches will include the following main types of immunotherapies: (1) targeting of myelin specific T cells: antigen-specific therapies (2) targeting of B cell and autoantibody responses (3) targeting of immunologic steps of disease pathology (4) targeting of reparative stages of disease: neurotrophic and neuroprotective, (5) global therapies: broad-based polydirectional strategies.