Currently, a head-to-head race for approval had initially developed between two under spotlight oral immunomodulatory agents-fingolimod and cladribine ( Figure 2 ) [131] . Fingolimod (FTY720/Gilenya, Novartis), an S1PR modulator [132] , is under the spotlight because it has completed phase III trials [133] and has been approved by the US Food and Drug Administration as the first oral, first-line treatment for relapsing MS [134, 135] . S1PR is mainly expressed by immune cells, neuronal cells, endothelial cells, and smooth muscle cells [136] [137] [138] [139] . The key roles of S1PR in angiogenesis, neurogenesis, and the regulation of immune cell trafficking, endothelial barrier function, and vascular tone were demonstrated with the genetic deletion of S1pr in a murine model [140] [141] [142] . The immunomodulatory effect of fingolimod acts in two pathways. In one pathway, it inhibits the function of S1PR, which facilitates the CC-chemokine receptor 7-(CCR7-) mediated retention of lymphocytes in the lymph nodes, including naïve T cells and central memory T cells, but not effective memory T cells. This significantly reduces the infiltration of inflammatory cells into the CNS [143, 144] and reduces the numbers of autoreactive Th17 cells that are recirculating via the lymph and blood to the CNS [145] [146] [147] . The second pathway prohibits neuroinflammation via the modulation of the . This activation results in the increased production of proinflammatory cytokines, which lead to the aberrant activation of Th1 and Th17 proinflammatory responses. Activated encephalitogenic adaptive immune effectors (such as Th1 cells, Th17 cells, CD8 + cells, and B cells) express surface molecules that allow them to penetrate the blood-brain barrier and to enter the central nervous system (CNS). The presence of autoreactive immune effectors, together with abnormally activated CNS astrocytes and microglia, leads to the increased production of reactive oxygen species, excitotoxicity, autoantibody production, and direct cytotoxicity, which are all involved in the demyelination and axonal and neuronal damage that is present in patients with MS. Potential therapeutic interventions at different levels of the immunopathological cascade are shown in the filled yellow boxes (cytotoxic T lymphocytes [ [55] .). S1PR1 expressed on oligodendrocytes, neurons, astrocytes, and microglia [76, 148, 149] . Another oral immunomodulatory drug Cladribine (2-chlorodeoxyadenosine) is a synthetic chlorinated deoxyadenosine analog [150] that is activated by intracellular phosphorylation in specific cell types, resulting in preferential and sustained reduction of peripheral T and B lymphocytes, mimicking the immunedeficient status of hereditary adenosine deaminase deficiency [151] . Orally administered cladribine shows significantly efficacy in patients with RR-MS [152] . Relative to placebo, oral cladribine reduces relapses by 55-58% and has an impact on disability progression and all MRI outcome markers in patients with RR-MS [152] [153] [154] . Nevertheless, to exactly weight the benefits of both novel immunomodultory agents against the potential risks is necessary and must be monitored continually.