An overview is presented on the metabolism of tricyclic antidepressants (TCAs), selective serotonin selective reuptake inhibitors (SSRIs), and newer antidepressants. Cytochrome P450 is the major enzyme system mediating the metabolism of these drugs. Results of in vitro and in vivo studies are reviewed, and the clinical implications with regard to drug-drug interactions and genetic polymorphisms are considered. Concerning TCAs, CYP2D6 plays a major role with regard to hydroxylation reactions. Additionally, a range of CYP enzymes participate in the N-demethylation pathways, e.g. CYP2C19, 1A2 and 3A4. With regard to the SSRIs and newer types of antidepressants, several CYP isoforms are involved, and CYP2D6 generally plays a minor role.