Hypoglycemia as a result of hyperinsulinism in the newborn (HI) is a clinically heterogeneous entity that presents a diagnostic and therapeutic challenge to the treating physician. Recent discoveries have shown that mutations in four different beta-cell genes cause HI. However, for many HI patients, the molecular etiology is unknown, and other genes might be involved. The study of the molecular biology of HI has led to a better understanding of pancreatic beta-cell physiology. In the future, this might result in the development of novel drugs for the treatment of both hyperinsulinism and non-insulin-dependent diabetes.