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Pharmacoresistant seizures and cytotoxic cerebral edema are serious complications of ischemic and traumatic brain injury. Intraneuronal Cl⁻ concentration ([Cl⁻]_i) regulation impacts on both cell volume homeostasis and Cl⁻-permeable GABA_A receptor-dependent membrane excitability. Understanding the pleiotropic molecular determinants of neuronal [Cl⁻]_i − cytoplasmic impermeant anions, polyanionic extracellular matrix (ECM) glycoproteins, and plasmalemmal Cl⁻ transporters − could help the identification of novel anticonvulsive and neuroprotective targets. The cation/Cl⁻ cotransporters and ECM metalloproteinases may be particularly druggable targets for intervention. We establish here a paradigm that accounts for recent data regarding the complex regulatory mechanisms of neuronal [Cl⁻]_i and how these mechanisms impact on neuronal volume and excitability. We propose approaches to modulate [Cl⁻]_i …