The control of insulin secretion from the pancreatic beta-cell involves a complex cascade of events in which the mitochondria play a central role. In the consensus model this role is essentially restricted to the production of ATP promoting membrane depolarisation and a rise in cytosolic [Ca2+]. Evidence for the generation of an additional mitochondrial factor implicated in metabolism-secretion coupling is provided in this review. Although not yet identified, the formation of this putative factor requires an increase of [Ca2+] in the mitochondrial matrix together with a supply of carbons to the tricarboxylic acid (TCA) cycle. In this model, calcium activates matrix dehydrogenases, in particular those of the TCA cycle. This enables the synthesis of the mitochondrial factor from the TCA cycle intermediates. Experimental evidence gathered in permeabilised cells largely supports this model.