In this issue of Cell Metabolism, Cabrera et al. (2008) provide evidence that glutamate can act as a positive autocrinesignal for a cell glucagon release in primates (human and monkey) and mice. Employing a variety of elegant experimental approaches, they show that glutamate is indeed secreted by a cells in response to low glucose concentration. Moreover,the secreted glutamate acts in a positive autocrine manner in vitro and in vivo through a cell ionotropic glutamate receptors (iGluRs). In human islets, glucagon release was stimulated by glutamate or by iGluR-specific agonists.