Drug-drug interactions continue to be underappreciated and misunderstood by most clinicians. Although life-threatening drug interactions are rare, serious clinical consequences, including altered drug response, poor tolerability with reduced medication adherence, and increased costs for care tied to the increased complexity of therapy, are fairly commonplace. Drug interactions may be further complicated by genetic differences in metabolic capacity. Patients who routinely require long-term treatment for depression have an increased likelihood of experiencing a drug-drug interaction since they will take over-the-counter and prescription medications for intercurrent and/or co-morbid illness. Antidepressants can be the object of drug interactions when their metabolic pathways are affected by other substances, or they can precipitate interactions by inhibiting enzyme pathways. Clinicians can improve the short- and long-term outcomes of patients with a depressive disorder by considering the possibility of drug-drug interactions both before prescribing a specific antidepressant and while monitoring for response, adverse effects and patient compliance.