A new era has been started in the morphological research of the human pancreatic islet parenchyma by the introduction of immunohistochemical (IHC) and modern morphometric techniques. This statement is illustrated by a report of two infants from two families with persistent neonatal hypoglycemia with hyperinsulinism, where specimens of pancreas, obtained at subtotal pancreatectomy, were analyzed together with autopsy specimens from age-matched "controls" (cardiac malformations). It was found that a nesidioblastosis-like picture occurred in the pancreas of the "controls", at least up to 6-7 months of age, and that in IHC stained sections this was indistinguishable from that observed in the endocrine pancreas of the hypoglycemic infants. Moreover, there was no difference in the total volume density of the islet parenchyma in pancreas of controls and hypoglycemic children when analyzed by morphometry. However, an increase in the relative incidence of insulin cells was found in the hypoglycemic infants as well as a moderate reduction of glucagon cells and a marked decrease of somatostatin cells. Clinically, some alleviation of the symptoms could be obtained by administration of glucagon and somatostatin, indicating that the hypothesis is correct that a defect in the maturation of the islet parenchyma during infancy may be a main pathogenetic factor in the syndrome. The familial occurrence of the disease may be more common than previously realized.