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Zn²⁺ is present at high concentrations in the synaptic vesicles of hippocampal mossy fibers. We have used Zn²⁺ chelators and the mocha mutant mouse to address the physiological role of Zn²⁺ in this pathway. Zn²⁺ is not involved in the unique presynaptic plasticities observed at mossy fiber synapses but is coreleased with glutamate from these synapses, both spontaneously and with electrical stimulation, where it exerts a strong modulatory effect on the NMDA receptors. Zn²⁺ tonically occupies the high-affinity binding site of NMDA receptors at mossy fiber synapses, whereas the lower affinity voltage-dependent Zn²⁺ binding site is occupied during action potential driven–release. We conclude that Zn²⁺ is a modulatory neurotransmitter released from mossy fiber synapses and plays an important role in shaping the NMDA receptor response at these synapses.