Patients who require long-term treatment for depression have an increased risk of experiencing drug interactions since they will take medications for intercurrent and/or co-morbid illness. Antidepressants can be the object of drug interactions by other substances, or they can precipitate interactions by inhibiting enzyme pathways. There is an increasing agreement about the importance of polymorphisms in cytochrome P450 enzymes and the effects of drug-drug interactions in relation to the incidence of adverse effects. Genetic test suitable for the routine laboratory are now available for some important metabolizing enzymes (e.g. CY2D6, CY2C19) identifying those individuals who are slow or fast metabolizers of certain drugs. Specific antidepressants differ in the interactions with CYP450 isoenzymes and in their susceptibility to drug-drug interactions. The main focus of this article is pharmacokinetic drug interactions of antidepressants. With that specific knowledge, clinicians can improve outcomes of depressed patients, by considering the possibility of drug interactions both before prescribing a specific antidepressant and while monitoring for response, adverse effects and patient compliance.