Recent studies with mutants of STIM and Orai have identified store-operated Ca²⁺ entry as an important regulator of neuronal function in Drosophila and mouse. Cellular Ca²⁺ imaging and electrophysiological studies demonstrate changes in ion channel function in neurons with loss of store-operated Ca²⁺ entry. Importantly, such changes are specific to neuronal subtypes. Transcriptomic and single-cell gene expression studies from the mouse brain identified wide, and isoform-specific differences, in expression of genes required for ER-store Ca²⁺ release and store-operated Ca²⁺ entry, across different neuronal classes. Loss of store-operated Ca²⁺ entry in neurons impacts neuronal gene expression profiles and includes genes encoding ion channels. The functional significance of store-operated Ca²⁺ entry across specific neuronal subtypes and in the context of neurodegenerative syndromes needs further study.