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Glucose is essential for cerebral metabolism. Unsurprisingly therefore, hypoglycemia may result in encephalopathy. Knowledge of the homeostatic mechanisms that maintain blood glucose concentrations within a tight range is the key for diagnosis and appropriate management of hypoglycemia. Neonatal hypoglycemia can be transient and is commonly observed in at-risk infants. A wide range of rare endocrine and metabolic disorders can present with neonatal hypoglycemia, of which congenital hyperinsulinism is responsible for the most severe form of hypoglycemia. Collection of appropriate blood samples for hormones and intermediary metabolites during an episode of hypoglycemia is critical for diagnosis and appropriate management. Prompt diagnosis with aggressive early intervention remains the mainstay of treatment to avert irreversible brain damage.