We report the presence of binding sites for permeant monovalent cations at the internal and external entrances to the channel of NMDA receptors. We measured the effects of changing internal cesium (Cs+) and external sodium (Na+) concentrations on the channel-blocking kinetics of the adamantane derivatives IEM-1754 and IEM-1857. Binding of Na+, or of Cs+ after it permeates the channel, to sites at the external channel entrance prevents blockers from entering the channel. Binding of Na+ to a blocked channel prevents blocker unbinding. Cs+ binding to a site at the internal channel entrance prevents IEM-1754 from occupying the deeper of its two sites of block. The results show the critical effects of permeant ions on the kinetics, affinity and voltage-dependence of channel blockers.