Hypoglycemia is a frequent problem in the neonatal period requiring close attention and intervention. Severe, persistent hypoglycemia can have various etiologies; one of the most common causes is hyperinsulinism. Nesidioblastosis, although rare, is the most common cause of hyperinsulinism in the neonate. If not detected early, nesidioblastosis can lead to brain damage and death secondary to severe hypoglycemia. The etiology of nesidioblastosis remains unclear. Treatment involves maintaining normal blood glucose levels; treatment modalities include high glucose infusion rates, use of medications, and surgical intervention. The article reviews the pathophysiology and treatment modalities for nesidioblastosis. A case study is also presented that describes the clinical presentation, treatment, surgical intervention, and postdischarge clinical course of an infant with nesidioblastosis.