- Powered by the mitochondrial membrane potential, Ca2+ permeates the mitochondria via a Ca2+ channel termed Ca2+ uniporter and is pumped out by a Na+/Ca2+ exchanger, both of which are located on the inner mitochondrial membrane. Mitochondrial Ca2+ transients are critical for metabolic activity and regulating global Ca2+ responses. On the other hand, failure to control mitochondrial Ca2+ is a hallmark of ischemic and neurodegenerative diseases. Despite their importance, identifying the uniporter and exchanger remains elusive and their inhibitors are non-specific. This review will focus on the mitochondrial exchanger, initially describing how it was molecularly identified and linked to a novel member of the Na+/Ca2+ exchanger superfamily termed NCLX. Molecular control of NCLX expression provides a selective tool to determine its physiological role in a variety of cell types. In lymphocytes, NCLX is essential for refilling the endoplasmic reticulum Ca2+ stores required for antigendependent signaling. Communication of NCLX with the store-operated channel in astroglia controls Ca2+ influx and thereby neuro-transmitter release and cell proliferation. The refilling of the Ca2+ stores in the sarcoplasmic reticulum, which is controlled by NCLX, determines the frequency of action potential and Ca2+ transients in cardiomyocytes. NCLX is emerging as a hub for integrating glucose-dependent Na+ and Ca2+ signaling in pancreatic beta cells, and the specific molecular control of NCLX expression resolved the controversy regarding its role in neurons and beta cells. Future studies on an NCLX knockdown mouse model and identification of human NCLX mutations are expected to determine the role of mitochondrial Ca2+ efflux in organ activity and whether NCLX inactivation is linked to ischemic and/or neurodegenerative syndromes. Structure-function analysis and protein analysis will identify the NCLX mode of regulation and its partners in the inner membrane of the mitochondria.