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 Ca(2+) signalling by either amplifying Ca(2+) entry through voltage-gated Ca(2+) channels by Ca(2+)-induced Ca(2+) release (CICR) or by producing local or global cytosolic calcium fluctuations following stimulation of metabotropic receptors through inositol-1,4,5-trisphosphate-induced Ca(2+) release (IICR). The ER Ca(2+) store emerges as a single interconnected pool, thus allowing for a long-range Ca(2+) signalling via intra-ER tunnels. The fluctuations of intra-ER free Ca(2+) concentration regulate the activity of numerous ER resident proteins responsible for post-translational protein folding and modification. Disruption of ER Ca(2+) homeostasis results in the developing of ER stress response, which in turn controls neuronal survival. Altered ER Ca(2+) handling may be involved in pathogenesis of various neurodegenerative diseases including brain ischemia and Alzheimer dementia.