Ca2+ plays a critical role in intracellular signaling and thus regulation of calcium balance is critical for the maintenance of this signaling function. 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. NaCX-1 is most prominently expressed in the heart where it plays a major role in excitation-contraction coupling. NACX-1 may also be a target for protection of the heart and brain from ischemia and reperfusion injury.