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Oligodendrocytes (OLs) are the myelinating cells of the central nervous system. Therapeutics that promote OL survival and remyelination are needed to restore neurological function in multiple sclerosis (MS). Sphingosine 1-phosphate (S1P) is a lipid metabolite that signals through five receptors, S1PR1-5. The MS drug Fingolimod is an S1PR agonist that suppresses neuroinflammation. A key question in current research is whether S1PR agonists also directly protect OLs and promote remyelination. However, the role for endogenous S1P, synthesized by sphingosine kinase 2 (SphK2), in OL survival and myelination has not been established. This thesis investigated the importance of SphK2 in OL survival and remyelination using the cuprizone mouse model of acute demyelination, followed by spontaneous remyelination. OL density and myelin protein levels did not differ between untreated wild-type (WT) and SphK2 knockout (SphK2−/−) mice. However, after cuprizone treatment, significantly greater demyelination and loss of mature OLs were observed in the corpus callosum and cerebral cortex of SphK2−/− compared to WT mice. Spontaneous remyelination occurred in WT but not SphK2−/− mice following cuprizone withdrawal, despite restoration of mature OL numbers in SphK2−/− mice. These results indicate that SphK2 is not necessary for proliferation and maturation of OL progenitor cells but is necessary for the synthesis of new myelin by mature OLs. Since S1PR5 is expressed exclusively by OLs, we also investigated whether S1PR1/5 agonist Siponimod and S1PR5-selective agonist A-971432 protect against myelin and OL loss in WT mice. Siponimod but not A-971432 protected against cuprizone-mediated OL loss, demyelination, astrogliosis, and microgliosis. Overall, this thesis demonstrates the importance of SphK2 for OL stress resistance and spontaneous remyelination. Future work will determine whether the S1P produced by SphK2 promotes remyelination through autocrine stimulus of OL S1P receptors.