For normal glucose homeostasis, insulin release by the pancreatic beta cell is vital. Until recently, it was thought that glucose-induced ionic events, such as closure of the ATP-sensitive K+ (KATP) channels, membrane depolarization, activation of the L-type voltage-dependent Ca2+ channels, Ca2+ influx and elevation of cytosolic free Ca2+, constitute the main signalling pathway in beta-cell stimulus-secretion coupling. However, since the discovery of 'non-ionic' glucose actions in the beta cell by the Aizawa and Henquin laboratories in 1991, data have accumulated that strongly indicate the physiological relevance of this signalling pathway. In this review, Toru Aizawa and colleagues discuss how the KATP channel-Ca2+ hypothesis was formulated, what was overlooked in the hypothesis, and then provide a comprehensive view of stimulus-secretion coupling in the beta cell, with an emphasis on non-ionic glucose actions.