Compared to typical antipsychotic drugs, clozapine produces a unique pattern of Fos-like immunoreactive neurons in the rat forebrain. It has been proposed, therefore, that this approach may be useful in identifying other agents with clozapine's therapeutic profile. In the present study, we examined the ability of olanzapine to increase the number of Fos-like immunoreactive neurons in the striatum, nucleus accumbens, lateral septal nucleus, and prefrontal cortex. Olanzapine (5, 10 mg/kg) produced dose-dependent increases in the number of Fos-positive neurons in the nucleus accumbens and lateral septal nucleus, important components of the limbic system that may mediate some of the therapeutic actions of neuroleptics. Olanzapine also produced dose-dependent increases in the number of Fos-positive neurons in the dorsolateral striatum, an effect that correlates with the ability of neuroleptics to produce extrapyramidal side-effects. The effects of olanzapine on regional c-fos expression are not therefore identical to clozapine, which is without effect in the dorsolateral striatum. However, olanzapine-induced increases in the dorsolateral striatum were considerably smaller than those generated in the nucleus accumbens suggesting that at low, potentially therapeutic doses olanzapine may not generate significant extrapyramidal side effects. Olanzapine also increased the number of Fos-positive neurons in medical prefrontal cortex, an action unique to clozapine and a few other atypical antipsychotics. These findings are consistent with the hypothesis that olanzapine is an atypical antipsychotic in the sense that it does not produce significant extrapyramidal side-effects at low therapeutic doses. However, extrapyramidal side-effects at higher doses can be predicted by these results. Finally, olanzapine's actions in the medial prefrontal cortex may be predictive of a clozapine-like profile with respect to actions on negative symptoms in schizophrenia. Additional clinical experience with olanzapine and other new antipsychotics is required to test the validity of these hypotheses.