Human EFCBP/NECAB family consists of important participants in neuronal calcium signaling, including EFCBP1/NECAB1, EFCBP2/NECAB2 and EFCBP3/NECAB3. NECAB1 was first identified as the target protein of synaptotagmin I C2A-domain by affinity chromatography, with its expression restricted to layer 4 cortical pyramidal neurons, inhibitory interneurons, and hippocampal CA2 pyramidal cells in mouse brain. The gene of the second member was cloned from mouse and initially named Necab. It encodes a 389-aa (NECAB2). NECAB2 was identified as a downstream target of Pax6 in mouse retina, which is involved in retinal development, as well as being a binding partner for the adenosine A2A receptor. Furthermore, an interaction between NECAB2 and metabotropic glutamate receptor 5 (mGluR5) was demonstrated in rat hippocampal pyramidal cells, possibly regulating mGluR5’s coupling to its signaling machinery. Finally, NECAB3, also known as XB51, was isolated as an interacting target for the neuron-specific X11-like protein and is possibly involved in the pathogenesis of Alzheimer’s disease.