The endoplasmic reticulum is one of the largest intracellular organelles represented by continuous network of cisternae and tubules, which occupies the substantial part of neuronal somatas and extends into finest neuronal processes. The endoplasmic reticulum controls protein synthesis as well as their post-translational processing, and generates variety of nucleus-targeted signals through Ca(2+)-binding chaperones. The normal functioning of the endoplasmic reticulum signalling cascades requires high concentrations of free calcium ions within the endoplasmic reticulum lumen ([Ca(2+)](L)), and severe alterations in [Ca(2+)](L) trigger endoplasmic reticulum stress response, manifested by either unfolded protein response (UPR) or endoplasmic reticulum overload response (EOR). At the same time, the endoplasmic reticulum is critically involved in fast neuronal signalling, by producing local or global cytosolic calcium signals via Ca(2+)-induced Ca(2+) release (CICR) or inositol-1,4,5-trisphosphate-induced Ca(2+) release (IICR). Both CICR and IICR are important for synaptic transmission and synaptic plasticity. Several special techniques allowing real-time [Ca(2+)](L) monitoring were developed recently. Video-imaging of [Ca(2+)](L) in neurones demonstrates that physiological signalling triggers minor decreases in overall intraluminal Ca(2+) concentration due to strong activation of Ca(2+) uptake, which prevents severe [Ca(2+)](L) alterations. The endoplasmic reticulum lumen also serves as a "tunnel" which allows rapid transport of Ca(2+) ions within highly polarised nerve cells. Fluctuations of intraluminal free Ca(2+) concentration represent a universal mechanism, which integrates physiological cellular signalling with protein synthesis and processing. In pathological conditions, fluctuations in [Ca(2+)](L) may initiate either adaptive or fatal stress responses.