Glucose is the main cerebral fuel throughout life. Inadequate cerebral glucose supply, due to recurrent episodes of severe hypoglycemia during the neonatal period or infancy, when the brain is still developing, lead to serious long-term neurological impairments, ranging from mild neurocognitive dysfunction to severe mental retardation, epilepsy, microcephaly or even hemiparesis or aphasia. Moreover, in the most common form of severe recurrent hypoglycemia of infancy due to hyperinsulinism, not only abnormalities in neurocognitive function, but also the later development of diabetes mellitus are observed. Furthermore, recurrent hypoglycemia, supervening as a side-effect of intensified insulin treatment in young diabetic children, may also induce mild neurocognitive dysfunction and, specifically, memory deficits that predispose these children to new hypoglycemic episodes and hypoglycemia unawareness. In conclusion, prompt and meticulous management of hypoglycemia and its prevention during the neonatal period, infancy and childhood constitute the main goal of physicians taking care of these patients in order to ascertain a long-standing quality of life devoid of long-term sequelae.