Hypoglycemia is especially dangerous to the developing brain of the newborn. While most causes of neonatal hypoglycemia are transient, those that persist can have devastating consequences. Therefore, it is of the utmost importance to identify, categorize, and appropriately treat these patients as promptly as possible. Most cases of persistent hypoglycemia seen in neonates are due to the overproduction of insulin. This condition was previously termed nesidioblastosis, and was thought to be due to diffuse hyperplasia of pancreatic islet cells. As we have learned more about the disease complex, this term is inaccurate. A more comprehensive and generally accepted term is congenital hyperinsulinism (CH). Insulinomas are a separate entity and are quite rare in childhood. They are not thought to be congenital and will not be addressed in this chapter [1]. Although CH may present throughout childhood and rarely even in adulthood, the most common age is within the neonatal period or infancy. The early-presenting cases invariably end up being more severe, more resistant to medical management, and more likely to require surgical intervention. Therefore, this chapter concentrates on CH specifically in the newborn patient, and highlights recent developments in genetics, diagnostic modalities, and surgical techniques that have improved the way clinicians manage this disease.