Calcium (Ca²⁺) is a versatile and important intracellular messenger, regulating a variety of cellular processes, including neurotransmission, muscle contraction, and signal transduction. A large family of EF-hand Ca²⁺-binding proteins that includes the well-known calmodulin mediates the various Ca²⁺ functions. Neuronal calcium sensor-1 (NCS-1/frequenin) is another Ca²⁺-binding protein that is mainly expressed in excitable cells. NCS-1 has been reported to interact with phosphatidylinositol 4-kinaseIII-β and several ion channels, thereby playing crucial roles in regulating neuronal functions, including synaptic transmission, learning and memory, and cell survival. Although NCS-1 is also highly expressed in young hearts, little was known about its cardiac functions until recently. By characterizing Ncs1-knockout mice, NCS-1 has recently been identified as a novel regulator of immature heart contraction and cardiac hypertrophy. Here, we will describe what is currently known about biochemical characteristics, multiple targets, and functional significance of NCS-1 in excitable cells, especially those found in brain and heart cells.