The Na⁺/Ca²⁺exchanger, an ion transport protein, is expressed in the plasma membrane (PM) of virtually all animal cells. It extrudes Ca²⁺ in parallel with the PM ATP-driven Ca²⁺ pump. As a reversible transporter, it also mediates Ca²⁺ entry in parallel with various ion channels. The energy for net Ca²⁺ transport by the Na⁺/Ca²⁺ exchanger and its direction depend on the Na⁺, Ca²⁺, and K⁺ gradients across the PM, the membrane potential, and the transport stoichiometry. In most cells, three Na⁺ are exchanged for one Ca²⁺. In vertebrate photoreceptors, some neurons, and certain other cells, K⁺ is transported in the same direction as Ca²⁺, with a coupling ratio of four Na⁺ to one Ca²⁺ plus one K⁺. The exchanger kinetics are affected by nontransported Ca²⁺, Na⁺, protons, ATP, and diverse other modulators. Five genes that code for the exchangers have been identified in mammals: three in the Na⁺/Ca²⁺ exchanger family (NCX1,NCX2, and NCX3) and two in the Na⁺/Ca²⁺ plus K⁺ family (NCKX1 and NCKX2). Genes homologous toNCX1 have been identified in frog, squid, lobster, andDrosophila. In mammals, alternatively spliced variants ofNCX1 have been identified; dominant expression of these variants is cell type specific, which suggests that the variations are involved in targeting and/or functional differences. In cardiac myocytes, and probably other cell types, the exchanger serves a housekeeping role by maintaining a low intracellular Ca²⁺concentration; its possible role in cardiac excitation-contraction coupling is controversial. Cellular increases in Na⁺concentration lead to increases in Ca²⁺ concentration mediated by the Na⁺/Ca²⁺ exchanger; this is important in the therapeutic action of cardiotonic steroids like digitalis. Similarly, alterations of Na⁺ and Ca²⁺ apparently modulate basolateral K⁺conductance in some epithelia, signaling in some special sense organs (e.g., photoreceptors and olfactory receptors) and Ca²⁺-dependent secretion in neurons and in many secretory cells. The juxtaposition of PM and sarco(endo)plasmic reticulum membranes may permit the PM Na⁺/Ca²⁺ exchanger to regulate sarco(endo)plasmic reticulum Ca²⁺ stores and influence cellular Ca²⁺ signaling.