Dopamine D2 receptor blockade is the main mode of antipsychotic action. The optimal occupancy of D2 receptors seems to be crucial to balancing efficacy and adverse effects such as extrapyramidal symptoms or hyperprolactinaemia. Partial D2 receptor agonism, different pre- and postsynaptic D2 receptor antagonism, serotonergic antagonism and modulation, and neurotrophic effects contribute to differentiated antipsychotic efficacy, less side effects, favourable effects on the negative and cognitive symptoms of schizophrenia, etc. In addition, neurotrophic effects of the 2nd generation antipsychotics increase neuronal plasticity and synaptic remodelling in the striatum, in the prefrontal cortex and hippocampus, which may normalise glutamatergic dysfunction and structural abnormalities postulated by the neurodevelopmental disconnection hypothesis of schizophrenia. We demonstrate these mechanisms using various antipsychotics and serotonin manipulations in animal models of schizophrenia (MK-801).