Repairing injured tissues / organs is one of the major challenges for the maintenance of proper organ function in adulthood. In mammals, the central nervous system including the spinal cord, once established during embryonic development, has very limited capacity to regenerate. In contrast, salamanders such as axolotls can fully regenerate the injured spinal cord, making this a very powerful vertebrate model system for studying this process. Here we discuss the cellular and molecular requirements for spinal cord regeneration in the axolotl. The recent development of tools to test molecular function, including CRISPR-mediated gene editing, has lead to the identification of key players involved in the cell response to injury that ultimately leads to outgrowth of neural stem cells that are competent to replay the process of spinal cord development to replace the damaged/missing tissue.