Antipsychotic agents have typically been viewed as acting through dopaminergic targets, although mounting evidence suggests that drugs such as clozapine may act on glutamatergic systems. In order to explore the effects of clozapine on the NMDA class of glutamate receptors, oocytes expressing the NMDA receptor NR1 subunit, coupled with different NR2 subunits, were exposed to clozapine and NMDA induced current was measured with two electrode voltage-clamp techniques. Our results indicate that clozapine inhibits the NMDA receptor, but that this inhibition is subunit specific, being significantly greater for receptors containing NR2A and NR2B than for those containing NR2C. Interestingly, the inhibition required pretreatment with clozapine before activation of the receptor with NMDA. In addition to providing mechanistic insights, this finding may help to explain divergent results in the literature regarding the effects of antipsychotic agents on glutamate receptors.