Lysolipids are important mediators of cellular communication in multiple physiological processes. Sphingosine-1-phosphate (S1P) is a major lysolipid in many organs, including the central nervous system (CNS). This commentary discusses recent findings on the role of S1P in regulating pain perception, and highlights advances and challenges in the field. S1P interacts with multiple cellular targets, including G-protein-coupled receptors. Known S1P receptors include five types, four of which are expressed in the CNS (S1P_1,2,3,5) where they are localized on neurons and glia. S1P receptor-mediated G-protein activation has been demonstrated throughout the CNS, including regions that regulate nociception. S1P receptors couple to multiple G-proteins to produce various intracellular responses, and can mediate both excitatory and inhibitory neuromodulation, depending on the receptor type and cellular context. Both antinociceptive and pro-nociceptive effects of S1P have been reported, and both actions can involve S1P₁ receptors. Current evidence suggests that antinociception is mediated by CNS neurons, whereas pro-nociception is mediated by primary afferent neurons or immune cells in the periphery, or CNS glia. Nonetheless, peripheral administration of the S1P_1,3,4,5 agonist pro-drug, FTY720, produces antinociception. FTY720 is approved to treat multiple sclerosis, and produces potent anti-inflammatory effects, which suggests potential utility for painful autoimmune diseases. Furthermore, evidence suggests that the S1P system interacts with other pain-modulatory systems, such as endogenous cannabinoid and opioid systems, and putative novel sphingolipid targets in the CNS. These findings suggest that drugs targeting the S1P system could be developed as novel analgesics, either as monotherapy or potential adjuncts to established analgesics.