AbstractDespite the availability of several classes of antiemetics, postoperative nausea and vomiting (PONV) remains a substantial burden for patients following surgery, resulting in patient dissatisfaction and prolonged stays in post‐anesthesia care units and ultimately increasing the cost of care. Enhanced recovery protocols and PONV management guidelines are now centered on the assessment of the individual patient's risk for developing PONV, as well as multimodal prophylaxis using antiemetics targeting different mechanisms of action. Over the last two decades, the neurokinin‐1 receptor (NK1R) has emerged as a therapeutic target for the management of PONV. This review of the literature explains the role of the NK1R and its ligand—substance P—in vomiting, describes the pharmacologic and pharmacokinetic properties of NK1R antagonists (NK1RAs) and summarizes the clinical evidence supporting NK1RAs for PONV prophylaxis in patients undergoing surgery. In particular, we discuss the therapeutic application of NK1RA in PONV prophylaxis protocols owing to their advantages over other antiemetic classes in efficacy, duration of efficacy, safety, pharmacology, and ease of administration. Future studies will be aimed at further investigating the efficacy and safety of NK1RA‐based multimodal combinations, particularly among vulnerable populations (e.g., children and elderly).