In the United States, approximately 15% of adults suffer from major depressive disorder (MDD), which results in an annual cost of over $200 billion per year. In the perioperative setting, MDD is associated with increased morbidity and mortality. The exact causes of the increase in adverse outcomes are unknown. Major depression affects virtually all major systems in the human body, and most antidepressants affect dopamine, norepinephrine, and serotonin levels or alter their target receptors. Unfortunately, anesthesia and medications used in the perioperative period affect the same neurotransmitters. As a result, patients with MDD are at an increased risk for cardiovascular effects, altered thermoregulation, and postoperative cognitive dysfunction. To determine when to continue or hold antidepressants preoperatively and avoid potential drug interactions, perioperative providers must understand the pharmacological action of antidepressants. This article reviews the pathophysiology of MDD, mechanism of action of antidepressants, and perioperative considerations for patients on antidepressant medications.