The Na⁺/Ca²⁺ exchanger (NCX) is an important electrogenic transporter in maintaining Na⁺ and Ca²⁺ homeostasis in a variety of mammalian organs, and is involved in the physiological and pathophysiological regulation of Ca²⁺ concentration in the myocardium. It can affect cardial structure, electrophysiology and contractile properties. The role of the NCX in heart cells following ischemia/reperfusion (IR) has been investigated using a number of in vitro and in vivo models. During ischemia, ionic disturbances favor Ca²⁺-influx mode activity as excess Na⁺ is extruded in exchange for Ca²⁺, giving rise to increased intracellular Ca²⁺ levels (Cai). This rise in Cai contributes to reversible cellular dysfunction upon reperfusion, such as myocardial necrosis, arrhythmia, systolic dysfunction and heart failure. We have reviewed the major in vivo and in vitro cardiac IR-related NCX studies in an attempt to clarify the functions of NCX in IR and conclude that recent studies suggest blockage of NCX has potential therapeutic applications. Although the use of different IR models, application of NCX stimulators and inhibitors, and development of NCX transgenic animals do help elucidate the role of this ion exchanger in heart cells, related mechanisms are not completely understood and clinically effective specific NCX inhibitors need further research.