Luigi Celio, Monica Niger, Francesca Ricchini, Francesco Agustoni Medical Oncology Unit 1, Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy Introduction: The second-generation 5-hydroxytryptamine-3 (5-HT3) receptor antagonist palonosetron is effective in the prevention of chemotherapy-induced nausea and vomiting (CINV) associated with highly and moderately emetogenic chemotherapy (HEC and MEC, respectively). In addition, palonosetron has been the first and, at present, the only 5-HT3 receptor antagonist to have a specific indication for the prevention of delayed CINV associated with MEC. The unique pharmacology of this antagonist is thought to partly explain its improved efficacy against delayed symptoms. Aims: To review the evidence underlying the use of palonosetron in preventing CINV. Evidence review: A recent meta-analysis consistently showed that palonosetron significantly increases the control of both emesis and nausea during the acute and delayed phases after single-day HEC or MEC. Consistent with these findings from trials that did not include an neurokinin-1 (NK-1) receptor antagonist, randomized controlled trials recently showed that a triple combination with palonosetron achieves significantly better control of delayed CINV, particularly delayed nausea, in patients undergoing HEC or the high-risk combination of an anthracycline and cyclophosphamide (AC). Evidence from randomized studies also supports palonosetron as a valuable option to reduce the total corticosteroid dose administered in patients undergoing multiple cycles of MEC or AC chemotherapy. Additional benefits of palonosetron include the lack of a warning on cardiac safety and no known clinically significant drug–drug interactions. Place in therapy and conclusion: Evidence currently available indicates that palonosetron significantly adds to the clinician’s ability to effectively control CINV in patients undergoing HEC or MEC. It is recommended in the international guidelines for the prevention of CINV caused by MEC. The high safety profile and the opportunity to reduce the total corticosteroid dose with no loss in efficacy against delayed CINV should also contribute to a wider use of palonosetron in clinical practice. Keywords: palonosetron, 5-HT3 receptor antagonist, CINV, moderately emetogenic chemotherapy, highly emetogenic chemotherapy, dexamethasone