Hyponatremia is the commonest electrolyte abnormality in hospitalized patients. When symptomatic (hyponatremic encephalopathy), the overall morbidity is 34%. Individuals most susceptible to death or permanent brain damage are prepubescent children and menstruant women. Failure of the brain to adapt to the hyponatremia leads to brain damage. Major factors which can impair brain adaptation include hypoxia and peptide hormones. In children, physical factors - discrepancy between skull size vs. brain size - are important in the genesis of brain damage. In adults, certain hormones - estrogen and vasopressin (elevated in virtually all cases of hyponatremia)- have been shown to impair brain adaptation, decreasing both cerebral blood flow and oxygen utilization. Initially, hyponatremia leads to an influx of water into brain, primarily to glial cells and largely via the water channel Aquaporin 4 (AQP4). Water is thus shunted into astrocytes, which swell, largely preserving neuronal cell volume. Depletion of AQP4 increases cerebral edema. The initial brain response to swelling is adaptation, utilizing the Na-K ATPase system to extrude cellular Na. In menstruant women, estrogen + vasopressin inhibits the Na-K ATPase system and decreases cerebral oxygen utilization, impairing brain adaptation. Cerebral edema compresses the respiratory centers and also forces blood out of the brain, both lowering arterial pO2 and decreasing oxygen utilization. The hypoxemia further impairs brain adaptation. Hyponatremic encephalopathy leads to brain damage when brain adaptation is impaired and is a consequence of both cerebral hypoxia and peptide hormones.