Persistent hypoglycemia in the neonate is most often caused by hyperinsulinemia. Recent discoveries in the molecular and biochemical regulation of insulin secretion have increased dramatically our understanding of disorders responsible for syndromes of hyperinsulinemic hypoglycemia. This article focuses on defects and disorders of the KATP channel, activating mutation of glucokinase and glutamate dehydrogenase, and other disorders that may be associated with specific phenotypes to permit appropriate targeted therapies. It is essential to evaluate these entities carefully because of the emerging evidence that at least half, if not more, have focal disease, which can be cured by local excision rather than diffuse disease, which may not be cured even after near total pancreatectomy with risk for future diabetes. Delay in diagnosis may be associated with developmental delay. The mechanisms of hypoglycemia remain incompletely understood.