The ATP-sensitive potassium (K_ATP) channel plays a crucial role in insulin secretion and thus glucose homeostasis. K_ATP channel activity in the pancreatic β-cell is finely balanced; increased activity prevents insulin secretion, whereas reduced activity stimulates insulin release. The β-cell metabolism tightly regulates K_ATP channel gating, and if this coupling is perturbed, two distinct disease states can result. Diabetes occurs when the K_ATP channel fails to close in response to increased metabolism, whereas congenital hyperinsulinism results when K_ATP channels remain closed even at very low blood glucose levels. In general there is a good correlation between the magnitude of K_ATP current and disease severity. Mutations that cause a complete loss of K_ATP channels in the β-cell plasma membrane produce a severe form of congenital hyperinsulinism, whereas mutations that partially impair channel function produce a milder phenotype. Similarly mutations that greatly reduce the ATP sensitivity of the K_ATP channel lead to a severe form of neonatal diabetes with associated neurological complications, whilst mutations that cause smaller shifts in ATP sensitivity cause neonatal diabetes alone. This chapter reviews our current understanding of the pancreatic β-cell K_ATP channel and highlights recent structural, functional and clinical advances.