Many of the molecules and pathways that enable regeneration are shared across different species. How these pathways are regulated—by the cell itself or by external factors—can determine a tissue’s ability to regenerate. By comparing the highly regenerative axolotl with mammals, which have limited regenerative abilities, we aim to identify the key differences that limit healing in mammals. Ultimately, our goal is to use these insights to develop strategies that could enhance regenerative processes in mammalian tissues.