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CYP2D6 is the major drug metabolizing enzyme involved in psychotropic metabolism. It is genetically polymorphic with 7% in the Caucasian population being poor metabolizers without any activity of this enzyme and 3% ultra rapid metabolizers with higher activity due to a gene duplication. Beside its expression in the liver, CYP2D6 was also shown to be active in several regions of the brain such as the hippocampus, thalamus, hypothalamus, and the cortex, There, CYP2D6 may be directly involved in the local metabolism of xenobiotics that cross the blood-brain barrier, as well as in the metabolic pathways of endogenous compounds such as regulatory substances like monoamines, neurosteroids, and endorphins. Brain-expressed CYP2D6 may play a role in the protection of the central nervous system from endogenous or exogenous neurotoxins and a possible association between environmental toxins and the genetics of sporadic Parkinson’s disease has been reported. The biotransformation of endogenous regulatory substances may constitute a possible genetic effects on personality and mental disorders. Prompted by early reports of shared affinity for ligands of the dopamine transporter, several studies investigated the association of the CYP2D6 polymorphism with schizophrenia, but mostly obtaining null results. Perhaps the most consistent data associating the CYP2D6 polymorphism and behavioral abnormalities are those linking it to suicide. To uncover the mechanisms behind gene-phenotype associations, it is important to acquire knowledge of the intermediate stages of the causal chain leading to the clinical manifestations of disease. Potential insights have been gained through the use of imaging genetics, and its recent application to the investigation of the effects of CYP2D6 polymorphism on brain function. We studied the genetic modulation of brain perfusion levels at rest, which may reşect an ongoing biological processes regulating the reactivity of the individual to emotional stimuli and the detection of signals evoking fear. These results suggested involvement of CYP2D6 in regions associated with alertness or serotonergic function. As a confirmation of these results, the function of the CYP2D6 genotype on brain activation during a working memory and an emotional face matching task was measured with fMRI. We confirmed a central nervous system effect of CYP2D6 activity in a large independent sample using a different imaging modality, and provide evidence that basic cognitive processes related to such as alertness may be impacted. A better understanding of these mechanisms will clarify in what situations pharmacogenetic testing may have practical implications not only for planning pharmacological therapy, but also to assess risk and vulnerability for mental disorders.