The pharmacodynamics of psychotropic drugs depend not only on their pharmacological profile but also on their availability in the target organ, the brain. The access of the drugs to the brain as well as that of their active metabolites is limited by their distribution in other organs, by their metabolism in the periphery and by mechanisms regulating their transport at the blood brain barrier. Cytochrome P-450 (CYP) is one of the principal phase-1 enzyme systems carrying out biotransformation of psychotropic drugs. The main CYP forms implicated in the metabolism of these pharmacological agents are CYP1A2, CYP2B6, CYP2D6, CYP2C9, CYP2C19 and CYP3A4/5, and several forms display a genetic polymorphism. Research about their expression, distribution and function in the brain is of clinical relevance as in situ, these enzymes may either deactivate or activate (by the formation of metabolites which quantitatively and/or qualitatively differ in their pharmacological profile from the parent compound) these drugs. Research strategies are based on the use of methods including molecular biology, protein analysis, and analysis of the activity of the enzymes [1]. A few studies suggest that some tricyclic antidepressants such as imipramine, desipramine and amitriptyline but also some antipsychotic drugs including haloperidol are submitted to cerebral biotransformation by CYP. Some amines are substrates of other enzymes such as MAO-A and MAO-B, as shown for citalopram, which is stereoselectively deaminated in animal and human brain. Drug metabolism in brain could potentially decrease the value of therapeutic drug monitoring (TDM) as this technique only includes the determination of drugs in peripheral blood and it does not allow considering drug metabolism in the central nervous system. However, present evidence suggests that psychotropic drug metabolism by CYP in brain is limited, but further research is necessary to demonstrate a clinically relevant impact of the biotransformation of psychotropic drugs in brain.