Key components of endoplasmic reticular (ER) Ca release and store-operated Ca entry (SOCE) are likely expressed in all metazoan cells. Due to the complexity of canonical Ca entry mechanisms in neurons, the functional significance of ER-Ca release and SOCE has been difficult to identify and establish. In this review we present evidence of how these two related mechanisms of Ca signaling impact multiple aspects of neuronal physiology and discuss their interaction with the better understood classes of ion channels that are gated by either voltage changes or extracellular ligands in neurons. Given how a small imbalance in Ca homeostasis can have strongly detrimental effects on neurons, leading to cell death, it is essential that neuronal SOCE is carefully regulated. We go onto discuss mechanisms of SOCE regulation identified in Drosophila and mammalian neurons. These include specific splice variants of STIM, different classes of membrane interacting proteins and an ER-Ca channel. So far these appear distinct from the mechanisms of SOCE regulation identified in non-excitable cells. Finally we touch upon the significance of these studies in the context of certain human neurodegenerative diseases. Abstract figure legend Store-operated Ca entry in neuronal cells is regulated by both positive (left) and negative regulators (right). This article is protected by copyright. All rights reserved.