© 2016 Wiley Periodicals, Inc. In the absence of the electrical signaling for which neurons are so highly specialized, GLIA rely on the slow propagation of ionic signals to mediate network events such as Ca2+ and Na+ waves. Glia differ from neurons in another important way, they are replete with a high density of ionic-transport proteins that are essential for them to fulfil their basic functions as guardians of the intra and extra-cellular milieux. Both the signaling and the homeostatic properties of glial cells are therefore particularly dependent upon the regulation of the two principle physiological metal cations, Ca2+ and Na+. For both ions, glia express high-affinity/low capacity ATP-fuelled pumps that can rapidly move small numbers of ions against an electro-chemical gradient. For both Ca2+ and Na+ regulation, a single transporter family, the Na+-Ca2+ exchanger (NCX), is used to maintain cellular ion homeostasis over the longer term and under conditions of prolonged or acute ionic dysregulation in astrocytes, oligodendroglia and microglia. Our understanding of glial NCX, both plasmalemmal and mitochondrial, is undergoing the kind of transformation that our understanding of glial cells, in general, has undergone in recent decades. These exchange proteins are becoming increasingly recognized for their essential roles in intracellular homeostasis while their signaling functions are starting to come to light. This review summarizes these key aspects and highlights the many areas where work has yet to begin in this rapidly evolving field. GLIA 2016;64:1646–1654.