Background The 5-HT3 antagonist, especially the second-generation of 5-HT3 antagonist palonosetron shows better efficacy against postoperative nausea and vomiting(PONV), its pharmacological mechanism and clinical efficacy were further investigated. Objective This paper sums up litures on its pharmacological mechanism and clinical efficacy on PONV prophylaxis. Content The second-generation 5-HT3 antagonist palonosetron has properties of greater receptor affinity, prolonged duration of action and few adverse effects. It blocks serotonin binding at vagal afferents in the gut and in the regions of the CNS involved in emesis, including the chemoreceptor trigger zone and the nucleus tractus solitarii, inhibits and emesis reflex, the high efficacy of palonosetron is being recognized. Trend This review summarizes its pharmacological mechanism of action, adverse effects, and clinical application on prevention of PONV, offering clinical reference to clinician to prevent PONV more reasonably.