Clozapine has multiple clinical advantages that differentiate it from typical neuroleptics but that it may share with other novel antipsychotic drugs such as risperidone and olanzapine. There may be more than one pharmacologic feature that contributes to its advantages in improving psychopathology, cognition, affect, tardive dyskinesia, etc. Clozapine has < 10 nM affinity for the serotonin (5-HT)2A, 5-HT2C, 5-HT6, 5-HT7, D4, m1, and alpha 1-adrenergic receptor but weak affinity for the D2 receptor. Current evidence suggests the 5-HT2A and D4 receptor antagonist properties of clozapine, together with its weak D2 blocking properties, contribute the most to its advantages and should be sought in drug development programs. However, the other effects of clozapine may also be contributory. Clozapine is effective in a variety of conditions and at a range of plasma levels. The effects that are important in various indications may differ.