The diagnosis of a hypoglycemic disorder requires a high level of suspicion, careful assessment of the patient for the presence of mediating drugs or predisposing illness, and, when indicated, methodic evaluation of the basis of well-defined diagnostic criteria. The diagnostic burden is heaviest for healthy-appearing persons with episodes of confirmed neuroglycopenia. The author's criteria for insulin mediation of hypoglycemia are plasma insulin of 6 microU/mL or higher (radioimmunoassay), C-peptide of 200 pmol/L or higher (ICMA), proinsulin of 5 pmol/L or higher (ICMA), beta OH butyrate of 2.7 mmol/L or lower, and generous (> or = 25 mg/dL) response of plasma glucose to intravenous glucagon administered when the patient is hypoglycemic. Sulfonylurea should be sought in the plasma of any hypoglycemic patient, especially by an assay which can detect the second generation of these drugs.