Powered by the mitochondrial membrane potential, Ca(2+) permeates the mitochondria via a Ca(2+) channel termed Ca(2+) uniporter and is pumped out by a Na(+)/Ca(2+) exchanger, both of which are located on the inner mitochondrial membrane. Mitochondrial Ca(2+) transients are critical for metabolic activity and regulating global Ca(2+) responses. On the other hand, failure to control mitochondrial Ca(2+) 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(+)/Ca(2+) 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 Ca(2+) stores required for antigen-dependent signaling. Communication of NCLX with the store-operated channel in astroglia controls Ca(2+) influx and thereby neuro-transmitter release and cell proliferation. The refilling of the Ca(2+) stores in the sarcoplasmic reticulum, which is controlled by NCLX, determines the frequency of action potential and Ca(2+) transients in cardiomyocytes. NCLX is emerging as a hub for integrating glucose-dependent Na(+) and Ca(2+) signaling in pancreatic β cells, and the specific molecular control of NCLX expression resolved the controversy regarding its role in neurons and β cells. Future studies on an NCLX knockdown mouse model and identification of human NCLX mutations are expected to determine the role of mitochondrial Ca(2+) 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.