The plasma membrane Na⁺/Ca²⁺ exchanger (NCX) plays a role in regulation of intracellular Ca²⁺ concentration via the forward mode (Ca²⁺ efflux) or the reverse mode (Ca²⁺ influx). To define the physiological function of the exchanger in vivo, we generated mice deficient for NCX2, the major isoform in the brain. Mutant hippocampal neurons exhibited a significantly delayed clearance of elevated Ca²⁺ following depolarization. The frequency threshold for LTP and LTD in the hippocampal CA1 region was shifted to a lowered frequency in the mutant mice, thereby favoring LTP. Behaviorally, the mutant mice exhibited enhanced performance in several hippocampus-dependent learning and memory tasks. These results demonstrate that NCX2 can be a temporal regulator of Ca²⁺ homeostasis and as such is essential for the control of synaptic plasticity and cognition.