Presynaptic terminal depolarization modulates the efficacy of transmitter release. Residual Ca2+ remaining after presynaptic depolarization is thought to play a critical role in facilitation of transmitter release, but its downstream mechanism remains unclear. By making simultaneous pre- and postsynaptic recordings at the rodent calyx of Held synapse, we have investigated mechanisms involved in the facilitation and depression of postsynaptic currents induced by presynaptic depolarization. In voltage-clamp experiments, cancellation of the Ca2+-dependent presynaptic Ca2+ current (IpCa) facilitation revealed that this mechanism can account for 50% of postsynaptic current facilitation, irrespective of intraterminal EGTA concentrations. Intraterminal EGTA, loaded at 10 mM, failed to block postsynaptic current facilitation, but additional BAPTA at 1 mM abolished it. Potassium-induced sustained depolarization of non-dialysed presynaptic terminals caused a facilitation of postsynaptic currents, superimposed on a depression, with the latter resulting from reductions in presynaptic action potential amplitude and number of releasable vesicles. We conclude that presynaptic depolarization bidirectionally modulates transmitter release, and that the residual Ca2+ mechanism for synaptic facilitation operates in the immediate vicinity of voltage-gated Ca2+ channels in the nerve terminal.