In this perspective, we discuss efforts to develop first-in-class KCC2 therapeutics, highlight some key insights gained from recent literature to provide a practical roadmap for therapeutically targeting KCC2 to treat neurological disorders, and discuss the translational considerations for advancing first- and best-in-class KCC2 potentiators into the clinic to address unmet medical needs of a variety of neurological disorder patients are discussed. This evidence concerns the gene SLC12A5 and nervous system disorder.