Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) which predominantly affect young adults and undergo heavy socioeconomic burdens. Conventional therapeutic modalities for MS mostly downregulate aggressive immune responses and are almost insufficient for management of progressive course of the disease. Mesenchymal stem cells (MSCs), due to both immunomodulatory and neuroprotective properties have been known as practical cells for treatment of neurodegenerative diseases like MS. However, clinical translation of MSCs is associated with some limitations such as short-life engraftment duration, little in vivo trans-differentiation and restricted accessibility into damaged sites. Therefore, laboratory manipulation of MSCs can improve efficacy of MSCs transplantation in MS patients. In this review, we discuss several novel approaches, which can potentially enhance MSCs capabilities for treating MS.