The plasma membrane Na+/Ca2+ (NaCX) exchangers mediate Na+-dependent Ca2+ efflux in a wide variety of cell types. NaCX can move Ca2+ either into or out of cells, depending on the net Na+, Ca2+, and K+ gradient across the membrane. In mammals, at least 5 distinct genes code for the exchangers: three NaCX (NaCX-1, NaCX-2, and NaCX-3), and two NaCKX (NaCKX-1 and NaCKX-2). NaCX-1 is most prominently expressed in the heart where it plays a major role in excitation-contraction coupling. NACX-1 may also play a role in protecting the heart and brain from ischemia and reperfusion injury.