It is accepted that insulin-secreting β-cells release insulin in response to glucose even in the absence of functional ATP-sensitive K + (K ATP )-channels, which play a central role in a ‘consensus model’ of secretion broadly accepted and widely reproduced in textbooks. A major shortcoming of this consensus model is that it ignores any and all anionic mechanisms, known for more than 40 years, to modulate β-cell electrical activity and therefore insulin secretion. It is now clear that, in addition to metabolically regulated K ATP -channels, β-cells are equipped with volume-regulated anion (Cl – ) channels (VRAC) responsive to glucose concentrations in the range known to promote electrical activity and insulin secretion. In this context, the electrogenic efflux of Cl – through VRAC and other Cl – channels known to be expressed in β-cells results in depolarization because of an outwardly directed Cl – gradient established, maintained and regulated by the balance between Cl – transporters and channels. This review will provide a succinct historical perspective on the development of a complex hypothesis: Cl – transporters and channels modulate insulin secretion in response to nutrients.