Inbred mouse strain comparisons are an important aspect of pharmacogenetic research, especially in strains known to differ in regard to specific neurotransmitter systems. DBA/2 mice differ from C57BL/6 mice in terms of both functional and anatomical characteristics of dopamine systems. Given the importance of D2 antagonism in the action of antipsychotic drugs and in theories regarding schizophrenia (i.e. the dopamine hypothesis), this study compared the discriminative stimulus properties of the atypical antipsychotic drug clozapine (CLZ) in C57BL/6 and DBA/2 inbred mice. DBA/2 and C57BL/6 mice were trained to discriminate 2.5 mg/kg of CLZ from vehicle in a two-lever drug discrimination procedure and tested with a variety of antipsychotic drugs and selective ligands. Both strains of mice readily acquired the CLZ discrimination. The atypical antipsychotic drugs olanzapine and risperidone fully substituted for CLZ in both DBA/2 and C57BL/6 mice, but ziprasidone fully substituted only in the C57BL/6 mice. The typical antipsychotic drug haloperidol produced partial substitution for CLZ in the DBA/2 mice, and the dopamine agonist amphetamine required a higher dose to reduce response rates significantly in DBA/2 mice as compared with C57BL/6 mice. Antagonism of serotonergic (5-HT2A/2B/2C) receptors with ritanserin and alpha1-adrenergic receptors with prazosin engendered CLZ-appropriate responding only in the C57BL/6 mice. Thus, while serotonergic and alpha-adrenergic antagonism were shown to be important for CLZ's discriminative cue in C57BL/6 mice, none of the selective ligands produced CLZ-appropriate responding in DBA/2 mice. Differences in dopamine-mediated functions between the two strains of mice may explain some of the findings in this study.