Among its many functions, the endoplasmic reticulum (ER) in eukaryotes serves as a store for intracellular Ca2+. In metazoan cells, there are two classes of ER membrane localized channels that release intracellular Ca2+ in response to external signals. ER-Ca2+ release is followed by extracellular Ca2+ entry through a process called store-operated Ca2+ entry (SOCE), essential for cellular Ca2+ signaling and homeostasis. Recent findings suggest that neuronal SOCE differs based on the nature of ER-Ca2+ release channels activated and the architecture of the ER across neuronal compartments. These properties determine the amplitude and time of ER-Ca2+ release and SOCE, which in turn determine activation of downstream effector molecules. The importance of these findings is discussed in the context of normal physiology and neurodegenerative conditions. Drugs targeting regulators of ER-Ca2+ release and SOCE show promise in terms of reverting symptoms of neurodegenerative conditions such as Alzheimers’ disease.