We propose an integrated kinetic model for the squid nerve Na+/Ca2+ exchanger based on experimental evidences obtained in dialyzed axons. This model satisfactorily explains the interrelationship between ionic (Na+i–H+i–Ca2+i) and metabolic (ATP, phosphoarginine (PA)) regulation of the exchanger. Data in dialyzed axons show that the Cai-regulatory site located in the large intracellular loop plays a central role in the modulation by ATP by antagonizing the inhibitory Na+i–H+i synergism. We have used the Nao/Nai exchange mode to unequivocally measure the affinity of the Cai-regulatory site. This allowed us to separate Cai-regulatory from Cai-transport sites and to estimate their respective affinities. In this work we show for the first time that under conditions of saturation of the Cai-regulatory site (10 μM Ca2+i, pHi 8.0), ATP have no effect on the Cai-transport site. In addition, we have expanded our equilibrium kinetic model of ionic and metabolic interactions to a complete exchange cycle (circular model). This model, in which the Cai-regulatory site plays a central role, accounts for the decrease in Nai inactivation, at high pHi, high Ca2+i, and MgATP. Furthermore, the model also predicts the net Ca2+ movements across the exchanger based on the exchanger complexes redistribution both during physiological and pathological conditions (ischemia).