Hypoglycemia in the pediatric population is a common finding important to recognize and manage to prevent brain injury. Recent advances in molecular genetics have provided new insight into its biochemical and physiologic basis and have led to more appropriate and specific treatment. Although a major cause of brain injury in pediatrics, the ability to predict the long-term outcome in these patients remains difficult. Identification of these at-risk individuals is important. The physiologic adaptations associated with transition from fetal to neonatal life are now better understood thus allowing for improved surveillance and management. Despite these advances, analytical limitations of point-of-care testing instruments at low glucose concentration continue to persist, This review aims to address these questions and provide an overview of pediatric hypoglycemia and the molecular pathways involved.