Ion channels play a key role in the regulation of insulin release. Conveying the signals associated with glucose metabolism, ATP-sensitive potassium (K_ATP) channels induce a depolarisation of the cell membrane which in turn regulates Ca²⁺ influx and Ca-dependent exocytosis of insulin-containing granules. Congenital hyperinsulinism is caused by channelopathies through loss-of-function mutations in the genes which encode K_ATP channels (ABCC8, KCNJ11) or by metabolopathies in which defects in glucose metabolism lead to altered channel activity. In both situations, b-cells no longer rest and are constitutively active with elevated levels of intracellular Ca²⁺ due to inappropriate closure of K_ATP channels. In contrast, gain-of-function defects in ABCC8 or KCNJ11 are a cause of type 2 diabetes, and neonatal diabetes. Through studies of the function of b-cells isolated from more than 140 patients following surgery, we have now documented the relationship between loss of K_ATP channel function and the histopathophysiology of CHI. This approach has allowed us to characterise a spectrum of defects related to impaired ion channel function, identify subsets of patients in which CHI is unrelated to defects in K_ATP channels and to critically examine the properties of b-cells isolated from the pancreas of focal CHI patients. Through a greater understanding of the ionic basis of CHI we have initiated studies related to the rescue of K_ATP channels in b-cells from patients and have begun to explore the rational basis of new therapeutic opportunities.