NCX proteins explore the electrochemical gradient of Na(+) to mediate Ca(2+)-fluxes in exchange with Na(+) either in the Ca(2+)-efflux (forward) or Ca(2+)-influx (reverse) mode, whereas the directionality depends on ionic concentrations and membrane potential. Mammalian NCX variants (NCX1-3) and their splice variants are expressed in a tissue-specific manner to modulate the heartbeat rate and contractile force, the brain's long-term potentiation and learning, blood pressure, renal Ca(2+) reabsorption, the immune response, neurotransmitter and insulin secretion, apoptosis and proliferation, mitochondrial bioenergetics, etc. Although the forward mode of NCX represents a major physiological module, a transient reversal of NCX may contribute to EC-coupling, vascular constriction, and synaptic transmission. Notably, the reverse mode of NCX becomes predominant in pathological settings. Since the expression levels of NCX variants are disease-related, the selective pharmacological targeting of tissue-specific NCX variants could be beneficial, thereby representing a challenge. Recent structural and biophysical studies revealed a common module for decoding the Ca(2+)-induced allosteric signal in eukaryotic NCX variants, although the phenotype variances in response to regulatory Ca(2+) remain unclear. The breakthrough discovery of the archaebacterial NCX structure may serve as a template for eukaryotic NCX, although the turnover rates of the transport cycle may differ ~10(3)-fold among NCX variants to fulfill the physiological demands for the Ca(2+) flux rates. Further elucidation of ion-transport and regulatory mechanisms may lead to selective pharmacological targeting of NCX variants under disease conditions.