In contrast to more traditional antipsychotic drugs such as haloperidol, atypical antipsychotics such as clozapine are characterised by low levels of extrapyramidal side effects (EPS) and improved clinical efficacy. This may result from increased binding to dopamine D4and serotonin 5-HT2Aand 5-HT2Creceptors concomitant with decreased dopamine D2receptor blockade, particularly of D2sites in the striatum where EPS are thought to originate.Although there is no genetic evidence for a direct role of variation in the D4receptor gene in schizophrenia, a role for variation in the 5-HT2Areceptor gene is supported by genetic and biochemical studies. This does not preclude the D4receptor as a major therapeutic target for antipsychotic drugs, especially since it is expressed predominantly in the cortex and limbic system, where the antipsychotic effects of drugs such as clozapine are thought to be mediated.As novel serotonin-dopamine receptor antagonists with defined pharmacological profiles become available, the careful analysis of the relationship between receptor binding profiles and efficacy will determine the most important receptor targets for improved antipsychotic action without the generation of EPS. Furthermore, the role of D4receptors as therapeutic targets will soon be determined by the use of selective ligands about to be introduced into clinical trials.