Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycmia in neonatles and children. The inappropriate secretion of insulin by the pancreatic β-cells produces recurrent hypoglycemia, which can lead to severe and permanent brain damage. CHI results from mutations in different genes that play a role in the insulin secretion pathway, and each differs in their responsiveness to medical treatment. Currently, the only available approved treatment for hyperinsulinism is diazoxide. Patients unresponsive to diazoxide may benefit from specialized evaluation including genetic testing and 18F-DOPA PET to identify those with focal forms of CHI. The focal forms can be cured by selective pancreatectomy, but the management of diazoxide-unresponsive diffuse CHI is a real therapeutic challenge. Current off-label therapies include intravenous glucagon, octreotide and long-acting somatostatin analogs; however, they are often insufficient, and a 98% pancreatectomy or continuous feeds may be required. For the first time in over 40 years, new drugs are being developed, but none have made it to market yet. In this review, we will discuss current on-label and off-label drugs and review the currently available data on the novel drugs under development.