There is currently insufficient evidence to support the clinical use of antidepressants-beyond controlled investigations-for treatment of acute, or prevention of chronic, postoperative pain. Multiple positive trials suggest the therapeutic potential of antidepressants, which need to be replicated. Other nontrial evidence suggests potential safety concerns of perioperative antidepressant use. Future studies are needed to better define the risk-benefit ratio of antidepressants in postoperative pain management. Higher-quality trials should optimize dosing, timing and duration of antidepressant treatment, trial size, patient selection, safety evaluation and reporting, procedure specificity, and assessment of movement-evoked pain relevant to postoperative functional recovery.