This paper presents the pharmacokinetic properties of newer second generation antidepressants, with an emphasis on the main metabolic pathways of drugs and metabolites as well as their effects on the cytochrome P450 enzymes. Except for Milnacipran all newer antidepressants are biotransformed in the presence of at least one cytochrome P450 izoenzyme. Drugs and their metabolites may be the substrates or inhibitors of cytochromes P450. The knowledge of drugs' metabolic pathways as well as the knowledge of substrates and inhibitors of izoenzymes assists in choice of a proper drug and its dose. It is particularly important in case of polypharmacotherapy when there is a high risk of adverse events. It is also important to remember about genetic polymorphism of some cytochrome P450 izoenzymes (CYP2D6, CYP2C19) that underlies the marked inpatient variability in drug metabolism.