The mitochondrial membrane potential that powers the generation of ATP also facilitates mitochondrial Ca2+ shuttling. This process is fundamental to a wide range of cellular activities, as it regulates ATP production, shapes cytosolic and endoplasmic recticulum Ca2+ signaling, and determines cell fate. Mitochondrial Ca2+ transport is mediated primarily by two major transporters: a Ca2+ uniporter that mediates Ca2+ uptake and a Na+/Ca2+ exchanger that subsequently extrudes mitochondrial Ca2+. In this minireview, we focus on the specific role of the mitochondrial Na+/Ca2+ exchanger and describe its ion exchange mechanism, regulation by ions, and putative partner proteins. We discuss the recent molecular identification of the mitochondrial exchanger and how its activity is linked to physiological and pathophysiological processes.