We study why adult mammalian skin sometimes heals by fibrosis and sometimes by regeneration. Rather than viewing regeneration as a primitive or developmentally restricted property, our work shows that regenerative healing in adult mammals is governed by discrete signaling circuits. We identified a neuro-immune axis involving TRPA1-positive sensory neurons, T cells, and granulocyte colony-stimulating factor that is required for scarless skin regeneration. We also established that age-associated loss of regenerative capacity is driven by systemic suppression of skin-derived SDF1. By combining these two pathways, we increased the frequency of complete skin regeneration in mice from 1% to 75%. These discoveries define tissue regeneration as an actively coordinated mammalian program rather than a passive developmental remnant.