Cardiac sarcolemmal Na(+)--Ca(2+) exchange is a central component of Ca2+ signaling essential for Ca2+ extrusion and contributing to a variable degree to the development of the systolic Ca2+ transient. Reports on differential gene expression of Na(+)--Ca2+ exchange in cardiac disease and the regulation of its thermodynamic equilibrium depending on intracellular gradients of ion concentrations between subcellular compartments have recently put a new complexion on Na(+)--Ca2+ exchange and its implications for excitation-contraction (E-C) coupling. Heart failure models and genetic approaches to regulate expression of the Na(+)--Ca2+ exchanger have improved our knowledge of exchanger function. Modest overexpression of the Na(+)--Ca2+ exchanger in heterozygous transgenic mice had minimal effects on E-C coupling and cardiac function. However, higher levels of Na(+)--Ca2+ exchange expression in homozygotes led to pathological hypertrophy and failure with an increased interaction between the L-type Ca2+ current and Na(+)--Ca2+ exchange and reduced E-C coupling gain. These results suggested that the Na(+)--Ca2+ exchanger is capable of modulating sarcoplasmic Ca2+ handling and at high expression levels may interact with the gating kinetics of the L-type Ca2+ current by means of regulating subsarcolemmal Ca2+ levels. Despite being a central component in the regulation of cardiac E-C coupling, a newly generated mouse model with cardiac-specific conditional knock-out of the Na(+)--Ca2+ exchanger is viable with unchanged Ca2+ dynamics in adult ventricular myocytes. Cardiac myocytes adapt well to knock-out of the exchanger, apparently by reducing transsarcolemmal fluxes of Ca2+ and increasing E-C coupling gain possibly mediated by changes in submembrane Ca2+ levels. For E-C coupling in the murine model, which relies primarily on sarcoplasmic Ca2+ regulation, this led to the suggestion that the role of Na(+)--Ca2+ exchange should be thought of as a Ca2+ buffering function and not as a major Ca2+ transporter in competition with the sarcoplasmic reticulum.