Enabling axon regeneration after central nervous system (CNS) injury remains a major challenge in neurobiology. One of the major differences between the injured peripheral nervous system (PNS) and CNS is the pro- and antiregenerative responses of their glial cell populations. In addition to intrinsic qualities of the neurons themselves, glial-driven changes to the neural environment have a significant impact on regenerative outcome. This Review presents a comparison of the glial response to injury between the CNS and PNS and highlights features of the PNS glial response that, with continued study, might reveal long-sought-after keys to achieving CNS repair.