The endoplasmic reticulum (ER) is a universal signalling organelle, which regulates a wide range of neuronal functional responses. Calcium release from the ER underlies various forms of intracellular Ca2+ signalling by either amplifying Ca2+ entry through voltage-gated Ca2+ channels by Ca2+-induced Ca2+ release (CICR) or by producing local or global cytosolic calcium fluctuations following stimulation of metabotropic receptors through inositol-1,4,5-trisphosphate-induced Ca2+ release (IICR). The ER Ca2+ store emerges as a single interconnected pool, thus allowing for a long-range Ca2+ signalling via intra-ER tunnels. The fluctuations of intra-ER free Ca2+ concentration regulate the activity of numerous ER resident proteins responsible for post-translational protein folding and modification. Disruption of ER Ca2+ homeostasis results in the developing of ER stress response, which in turn controls neuronal survival. Altered ER Ca2+ handling may be involved in pathogenesis of various, neurodegenerative diseases including brain ischemia and Alzheimer dementia.