Hyperinsulinism (HI) is the most common cause of hypoglycemia in the newborn period and can be transient or persistent. Neonatal HI can cause significant morbidity and mortality if not recognized and carefully treated. Successful treatment of hyperinsulinism can be painstaking. Management demands 1) rigorous attention to blood glucose monitoring, 2) an attempt to restore normal or near-normal fasting tolerance, 3) preservation of a child’s ability and desire to feed, 4) establishment of a manageable home regimen that allows normal childhood development, and 5) alertness to the psychosocial stresses chronic illness imposes upon a family of a child. The discovery of a number of the genetic mutations responsible for congenital hyperinsulinism is allowing a more methodical and thoughtful approach to diagnosis and management. Identification of autosomal recessive mutations of the sulfonylurea receptor/potassium channel complex and of autosomal dominant gain of function mutations of glutamate dehydrogenase and glucokinase has provided powerful insight into the mechanism of the disease as well as into normal regulation of insulin secretion. Unfortunately, much has yet to be learned: uncharacterized forms of hyperinsulinism remain and the limited therapeutic armament is frequently ineffective.