Objective: The purpose of this study is to systematically review the evidence of palonosetron in chemotherapy-induced nausea and vomiting (CINV) and to understand its place in therapy. Methods: The English-language literature in OVID and Cochrane databases were searched using the following terms: palonosetron, antiemetics, CINV, and delayed. Of the 168 abstracts identified, 3 pivotal trials were deemed relevant by 2 independent reviewers. Guidelines from the American Society of Clinical Oncology, National Comprehensive Cancer Network (NCCN), and Multinational Association of Supportive Care in Cancer and the Food and Drug Administration (FDA) reviewers' comments on palonosetron were also obtained. Results: The trials, all non-inferiority studies, compared palonosetron 0.25mg to single-dose intravenous ondansetron or dolasetron. Two studies involved moderately emetogenic regimens. Palonosetron 0.25mg was associated with a significantly higher complete response (CR) rate in the delayed phase compared to ondansetron (74.1% vs. 55.1%, p=0.001) and dolasetron (54.0% vs. 38.7%, p=0.004). The CR rate with palonosetron 0.25mg in the acute phase was significantly higher than ondansetron (81.0% vs. 68.6%, p=0.009), but only numerically better than dolasetron (63.0% vs. 52.9%, p=0.049). In the trial with highly emetogenic agents, CR rates were comparable between palonosetron 0.25mg and ondansetron in both the acute (59.2% vs. 57.0%, p=0.701) and delayed (45.3% vs. 38.9%, p=0.180) phases. The FDA considered the CINV claims relative to placebo due to lack of approval of comparators for delayed CINV. Because of its long half-life, NCCN guidelines indicated that single-dose palonosetron could be considered at the start of a multi-day chemotherapy regimen instead of multiple daily doses of other 5-HT3-RAs; however, none of the guidelines designated a preferred 5-HT3-RA. Conclusion: 5-HT3-RAs can be considered clinically interchangeable. While palonosetron may provide convenience by avoiding the need for repeat daily dosing, this needs to be balanced against its additional cost given the advent of generic 5-HT3-RAs.