Congenital hyperinsulinism (HI) is defined as being “diazoxide-unresponsive” if the hypoglycemia persists despite maximum doses of diazoxide for at least five days. Inactivating mutations in the genes encoding the two subunits of the beta-cell ATP-sensitive potassium (KATP) channel are the most frequent cause of diazoxide-unresponsive hyperinsulinism. Children with KATPHI typically present at birth with severe hypoglycemia. Genetic testing can be used to identify children with focal KATPHI and 18F-DOPA-PET imaging aids with focal lesion localization for curative surgery. A less common form of diazoxide-unresponsive HI is caused by activating mutations in glucokinase (GCK). Clinical phenotypes in children with GCK HI vary, but may be diazoxide-unresponsive and medically uncontrollable, requiring pancreatectomy. Approximately ten percent of diazoxide-unresponsive HI cases are of unknown genetic etiology. The overall goal in the management of infants with diazoxide-unresponsive HI is to identify those with focal HI and to find an effective treatment regimen for those that cannot be cured by surgery (diffuse HI).