Fingolimod (FTY720) and its phosphorylated form FTY720P are modulators of sphingosine-1-phosphate (S1P) receptors, which are G-protein coupled receptors linked to cell migration and vascular maturation. The efficacy of FTY720 in autoimmune diseases such as multiple sclerosis and its animal models has been attributed to its inhibition of lymphocyte trafficking to target organs. In this study, we examined the role of S1P receptors in cultured rat oligodendrocytes (OLGs) and OLG progenitor cells (OPCs) using the active phosphorylated form of FTY720. We found that (1) FTY720P improves the survival of neonatal rat OLGs during serum withdrawal, which is associated with the phosphorylation of extracellular signal regulated kinases (ERK1/2) and Akt; (2) FTY720P regulates OPC differentiation into OLGs in a concentration-dependent manner; and (3) S1P receptors are differentially modulated by platelet-derived growth factor (PDGF) resulting in downregulation of S1P5 and upregulation of S1P1 in OPCs. In addition, siRNA studies revealed that S1P1 participates in PDGF-induced OPC mitogenesis. We conclude that S1P1 and S1P5 serve different functions during oligodendroglial development, and possibly during remyelination.