Introduction: Multiple sclerosis (MS) is an autoimmune disease of central nervous system that is characterized by the progressive loss of myelin. In addition to immunoregulatory properties, novel MS therapies promote myelin repair activities. Mesenchymal stem cells (MSCs) have been viewed as a potent tool for regenerative and immunosuppressive functions, indicating a potential therapy for MS. MSCs have immunological functions which are exerted by direct cell-to-cell contacts, secretion of stimulatory and inhibitory cytokines, and/or a combination of both mechanisms. Therefore, these cells can inhibit differentiation and proliferation of T-cell and stimulate the Th2 and regulatory T-cells through inhibitory effects on the immune system. Conclusion: In the current review, we discuss the mechanisms underlying the immunomodulatory effect of MSCs in different experimental models of MS.