Many aspects of neuronal activity are regulated by calcium signals. The transduction of temporally and spatially distinct calcium signals requires the action of calcium sensor proteins including various EF-hand containing calcium-binding proteins. The Neuronal Calcium Sensor (NCS) family proteins have begun to emerge as key players in neuronal function. Many of these proteins are expressed predominantly or only in neurons sometimes with cell-specific patterns of expression. The NCS protein family is encoded by 14 genes in the human genome that possess four EF hand domains of which 2 or 3 bind calcium. The NCS proteins are high-affinity calcium-binding proteins that act as calcium sensors rather than calcium buffers as they undergo conformational changes on calcium-binding and regulate target proteins. Their ability to associate with membranes either constitutively or in response to calcium elevation allows the NCS proteins to discriminate between different spatial and temporal patterns of calcium signals. Several of the NCS proteins show changes in expression levels in specific disease states. Recent work has established several physiological roles of these proteins including diverse actions on gene expression, ion channel function, membrane traffic of ion channels and receptors and in the control of apoptosis. The NCS proteins act as calcium sensors for diverse functions and also as regulators of calcium signals through their effects on ion channels.