Synaptic transmission provides the fundamental mechanisms for integrative processes in neuronal networks. Efficacy of synaptic transmission is directly controlled by the amount of neurotransmitter released into synaptic cleft. The release of the neurotransmitter, in turn, is regulated by several molecular cascades expressed in the presynaptic terminal. Activity of these cascades is regulated by the concentration of free calcium ions ([Ca²⁺]i) within the presynaptic terminal, and therefore an increase of [Ca²⁺]i in the presynaptic compartment controls neurotransmitter release. Elevation of [Ca²⁺]i in the presynaptic terminal results from Ca²⁺ entry through the plasmalemmal voltage-gated calcium channels, however Ca²⁺ release from the endoplasmic reticulum (ER) calcium store may also contribute towards presynaptic [Ca²⁺]i signals. In this review we summarize data supporting the importance of the ER Ca²⁺ release in regulation of neurotransmitter release.