Sphingosine 1-phosphate (S1P) is a biologically active lysophospholipid that transmits signals through a family of five G-protein-coupled receptors to regulate cell proliferation, migration, cytoskeletal organization, and differentiation. S1P5 can couple with Gi/o and G12/13, and it mediates S1P induced adenylate cyclase inhibition and Ca2+ mobilization like the other S1P receptors. However, unlike the other S1P receptors, it mediates inhibition of MAPK activation and cell proliferation. S1P5 is predominantly expressed in the white matter tracts and oligodendrocytes and is particularly abundant in the anterior commissure, corpus collosum, and optic tract. S1P induces process retraction in pre-oligodendrocytes and supports cell survival in mature oligodendrocytes by activating S1P5, which indicates a role for S1P5 in maturation and myelination of oligodendrocytes.