The clinical challenge posed by spinal cord injury (SCI) remains a significant and unresolved issue. Engineering a treatment for SCI will require biological repair interventions that restore connectivity through or around lesions. Using a combination of advanced neuroanatomical viral tract tracing, projection-specific and comparative single-nucleus RNA sequencing, bioinformatic techniques, we recently identified a molecularly defined subpopulation of excitatory projection neuron in the mid-thoracic spinal cord that extend axons to the lumbar spinal cord where walking execution centers reside. We targeted these neurons for regeneration using specifically required chemoattractive growth factors to stimulate these specifically targeted intrinsic axons to regrow to their natural terminal regions in the lumbar spinal cord and found that this regeneration reverses paralysis following anatomically complete SCI. However, this type of lesion is less common in humans, and the interventions required to achieve it are multiple and rely on complex genetic manipulations, the type of which should be kept to a required minimum for clinical translation. As SCI lesion compartments dictate and restrict the required repair strategy, it is essential to understand the mechanisms and neuronal subpopulations necessary to achieve repair and restoration of walking following increasingly severe injuries at different timepoints. Together, these findings will provide the foundation for developing gene therapy techniques suitable for clinical application to repair the injured human spinal cord across various injury severities.