We have previously demonstrated that rat cerebellar type-1 astrocytes express a very active Na+/Ca2+ exchanger which accounts for most of the total plasma membrane Ca2+ fluxes and for the clearance of Cai 2+ induce by physiological agonist. In this chapter, we have explored the mechanism by which the reverse Na+/Ca2+ exchange is involved in agonistinduced Ca2+ signalling in rat cerebellar astrocytes. Laser-scanning confocal microscopy experiments using immunofluorescence labelling of Na+/Ca2+ exchanger and RyRs demonstrated that they are highly co-localized. The most important finding presented in this chapter is that L-glutamate activates the reverse mode of the Na+/Ca2+ exchange by inducing a Na+ entry through the electrogenic Na+-glutamate co-transporter and not through the ionophoric L-glutamate receptors as confirmed by pharmacological experiments with specific blockers of ionophoric L-glutamate receptors, electrogenic glutamate transporters and the Na/Ca exchange.H. Rojas; C. Colina; M. Ramos; E. Jaffe; C. Caputo; R. Di Polo. Laboratorio de Fisiología Celular, Centro de Biofísica, Instituto Venezolano de Investigaciones Científicas (IVIC), Caracas, Venezuela e-mail: rdipolo@gmail.com Gustavo. Benaim Laboratorio de Señalización Celular, Instituto de Estudios Avanzados (IDEA), Caracas, Venezuela.