Abstract: Herein, the rationale and supporting evidence for the promise of developing K+/Cl− co-transporter-2 (KCC2) neuromodulatory therapies for spinal cord injury (SCI) is discussed. SCI is commonly a life-changing, unforeseen neurotrauma that has devastating consequences for the injured person, their families and society as a whole. Because less than 1% of patients have a complete recovery, the vast majority of people after SCI have significant disabilities and can be entirely dependent upon others for assistance in their activities of daily living. The socioeconomic costs are a significant global burden, with SCI often occurring in adults during their peak earning years. Currently, there are no approved drugs that improve functional outcomes for people with SCI. Therefore, SCI commonly leads to a lifetime of disability, and new therapeutic approaches are urgently needed.