Like for other drugs, non-compliance to the pharmacological treatment is an important problem during therapy with antipsychotics. Therapeutic drug monitoring (TDM) can be useful for detecting non or poor compliance. However, while undetected plasma levels can most often be used as a proof of non-compliance (provided the use of sensitive analytical methods), low plasma levels could be due either to partial compliance and/or rapid metabolism. In vitro studies, as well as in vivo pharmacogenetic studies with phenotyping and genotyping tests, have considerably improved our knowledge on the metabolism of antipsychotics, in particular on the implications of cytochromes P450 isozymes. The pharmacokinetics of atypical antipsychotics (clozapine, olanzapine, risperidone, quetiapine, aripiprazole, sertindole and amisulpride) will be addressed, with a particular emphasis on the CYP isoforms involved in their metabolism. Examples will be given on the possible genotyping and/or phenotyping tests to be used, in addition to TDM, for determining the patients' metabolizer status (i.e slow, extensive, rapid metabolizer) and how the use of these tests could optimize antipsychotic drug treatment, and rationalize the choice of the drugs. Clinical examples will be shown of patients with demonstrated rapid metabolism of one antipsychotic, leading to poor or non-response, who had their antipsychotic doses increased to very high levels, or who had their metabolism blocked by the administration of comedications, or who were successfully switched to another antipsychotic, taking advantage of our current knowledge on the drug's metabolic and renal clearance.