The present review discusses the history and paradigm of the conditioned avoidance response (CAR) in rats for the detection of potential antipsychotic activity of drugs. In addition, the role of dopamine (DA) D2, serotonin (5-HT)2A/2C, alpha1, 5-HT1A, DA D4, muscarinic and glutamate receptors in the suppression of CAR induced by various classes of drugs is evaluated. Finally, data investigating brain sites of action for the mediation of CAR behavior is discussed. It is concluded that the CAR test, originally found to be sensitive for the detection of antipsychotic drugs with high affinity as antagonists for brain dopamine receptors, is also sensitive for the detection of potentially antipsychotic compounds acting primarily via neurotransmitter receptors other than the DA D2 receptor. Furthermore, the review confirms the importance of the nucleus accumbens(shell) in the mediation of effects on CAR produced by traditional, as well as atypical antipsychotic drugs.