Atypical antipsychotic drugs related to clozapine may be distinguishable from typical antipsychotic drugs by having a greater potency in vitro at serotonin2 (5-HT2) receptors relative to dopamine2 (D2) receptors. The in vivo potencies of 10 typical and 10 putative atypical antipsychotic drugs in occupying D2 and 5-HT2 receptors in rat brain are reported here. There is no significant difference in the average potency of the two groups of antipsychotic drugs in preventing the in vivo binding of N-[3H] methylspiperone to 5-HT2 receptors in the cortex. However, the average potency of the atypical antipsychotic drugs is about 8-fold less than typical antipsychotic drugs in preventing N-[3H] methylspiperone binding to D2 receptors in the striatum. Thus, all of the atypical antipsychotic drugs that are clozapine-like have a greater relative affinity in vivo for the 5-HT2 than the D2 receptor. As a group, the typical antipsychotic drugs tend to be equipotent at both receptors. The average relative potency of the group of typical antipsychotic drugs at 5-HT2 vs. D2 receptors is essentially equal when examined in vivo vs. in vitro. Atypical antipsychotic drugs are slightly but significantly more potent in vivo at D2 receptors in the olfactory tubercle than the striatum. For only the typical antipsychotic drugs, the in vivo and in vitro potencies in occupying D2 receptors are correlated with their average clinical dosage. Thus, the relative in vivo potency of clozapine-related drugs at 5-HT2 vs. D2 receptors may help identify these compounds as atypical antipsychotic drugs.