Under physiologic conditions, glucose plays a critical role in providing energy to the central nervous system. A precipitous drop in the availability of this substrate results in dramatic symptoms that signal a medical emergency and warrant immediate therapy aimed at restoring plasma glucose to normal levels. A systemic approach to the differential diagnosis is useful in identifying the cause of hypoglycemia. Once established, a specific and/or definitive intervention that addresses that underlying problem can be implemented. In most cases, this systemic approach to diagnosis and therapy is rewarded with a good outcome for the patient.