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Multiple sclerosis (MS) is an autoimmune inflammatory disease characterized by demyelination, axonal loss, and synaptic impairment in the central nervous system (CNS). The available therapies aim to reduce the severity of the pathology during the early inflammatory stages, but they are not effective in the chronic stage of the disease. In this phase, failure in endogenous remyelination is associated with the impairment of oligodendrocytes progenitor cells (OPCs) to migrate and differentiate into mature myelinating oligodendrocytes. Therefore, stimulating differentiation of OPCs into myelinating oligodendrocytes has become one of the main goals of new therapeutic approaches for MS. Different disease-modifying therapies targeting sphingosine-1-phosphate receptors (S1PRs) have been approved or are being developed to treat MS. Besides their immunomodulatory effects, growing evidence suggests that targeting S1PRs modulates mechanisms beyond immunomodulation, such as remyelination. In this context, this review focuses on the current understanding of S1PR modulators and their direct effect on OPCs and oligodendrocytes. This work was funded by "stichting charcot foundation" and "FWO". Vanmierlo, T (corresponding author), Hasselt Univ, Biomed Res Inst, Neuroimmune Connect & Repair Lab, B-3500 Hasselt, Belgium ; Maastricht Univ, Sch Mental Hlth & Neurosci, European Grad Sch Neurosci, Dept Psychiat & Neuropsychol, NL-6200 MD Maastricht, Netherlands. roggeri@difar.unige.it; melissa.schepers@uhasselt.be; assia.tiane@uhasselt.be; ben.rombaut@uhasselt.be; lieve.vanveggel@uhasselt.be; niels.hellings@uhasselt.be; jos.prickaerts@maastrichtuniversity.nl; pittalug@difar.unige.it; tim.vanmierlo@uhasselt.be