Astrocytes do not merely serve as the supporting cast and scenery against which starring roles would be played by neurons. Rather, these glial cells are intimately involved in many of the brain's functions by responding to neuronal activity and modulating it. Such interplay between two principle neural cells, neurons and astrocytes, is evidenced in bi-directional glutamatergic astrocyte-neuron signaling. A key feature in this signaling pathway is astrocytic excitability based on variations of cytosolic Ca2+. It enables astrocytes, through the activation of their glutamatergic receptors, to respond to the same signal used by nearby neurons in synaptic transmission. Furthermore, increases in cytosolic Ca2+ in astrocytes can subsequently lead to Ca2+-dependent exocytotic secretion of gliotransmitter glutamate that in turn can signal to adjacent neurons. Astrocytic secretory machinery includes an assortment of exocytotic proteins which governs a merger of secretory vesicles to the plasma membrane. A cumulative knowledge on astrocytic excitability will aid better understanding of operating procedures in the brain in health and disease. © 2012 Elsevier Ltd. All rights reserved.