Neuroglial cells are homeostatic neural cells. Generally, they are electrically non-excitable and their activation is associated with the generation of complex intracellular Ca2+ signals that define the “Ca2+ excitability” of glia. In mammalian glial cells the major source of Ca2+ for this excitability is the lumen of the endoplasmic reticulum (ER), which is ultimately (re) filled from the extracellular space. This occurs via store-operated Ca2+ entry (SOCE) which is supported by a specific signaling system connecting the ER with plasmalemmal Ca2+ entry. Here, emptying of the ER Ca2+ store is necessary and sufficient for the activation of SOCE, and without Ca2+ influx via SOCE the ER store cannot be refilled. The molecular arrangements underlying SOCE are relatively complex and include plasmalemmal channels, ER Ca2+ sensors, such as stromal interaction molecule, and possibly ER Ca2+ pumps (of the SERCA type). There are at least two sets of plasmalemmal channels mediating SOCE, the Ca2+ -release activated channels, Orai, and transient receptor potential (TRP) channels. The molecular identity of neuroglial SOCE has not been yet identified unequivocally. However, it seems that Orai is predominantly expressed in microglia, whereas astrocytes and oligodendrocytes rely more on TRP channels to produce SOCE. In physiological conditions the SOCE pathway is instrumental for the sustained phase of the Ca2+ signal observed following stimulation of metabotropic receptors on glial cells. Generally, they are electrically non-excitable and their activation is associated with the generation of complex intracellular Ca2 + signals that define the “Ca2 + excitability” of glia. In mammalian glial cells the major source of Ca2 + for this is via lumen of the endoplasmic reticulum (ER), which is ultimately (re) filled from the extracellular space. This occurs via store-operated Ca2 + entry (SOCE) which is supported by a specific signaling system connecting the ER with plasmalemmal Ca2 + entry. Here, emptying of the ER Ca2 + store is necessary and sufficient for the activation of SOCE, and without Ca2 + influx via SOCE the ER store can not be refilled. The molecular relationship underlying SOCE is relatively complex and include plasmalemmal channels, ER Ca 2+ sensors, such as stromal interaction molecule, and possibly ER Ca2 + pumps (of the SERCA type). There are at least two sets of plasmalemmal channels mediating SOCE, the Ca 2, -release activated channels, Orai, and transient receptor potential (TRP) channels. However, it seems that Orai is predominantly expressed in microglia, but astrocytes and oligodendrocytes rely more on TRP channels to produce SOCE. In physiological conditions the SOCE pathway is instrumental for the sustained phase of the Ca 2+ signal observed following stimulation of metabotropic receptors on glial cells.