Significant progress has been made in the development of effective, convenient and well-tolerated means to prevent chemotherapy-induced nausea and vomiting (CINV). Nevertheless, a substantial minority of patients continue to have suboptimal antiemetic control, and additional treatment approaches are needed. One avenue of investigation being pursued involves the evaluation of a new 5-hydroxytryptamine (5-HT(3)) receptor antagonist (palonosetron) that differs from available serotonin antagonists in its markedly longer half-life (40 h) and greater binding affinity for the type-3 serotonin receptor. Analysis of available clinical data demonstrates that palonosetron is an active and well-tolerated new 5-HT(3) antagonist. Moreover, single-dose palonosetron, prior to chemotherapy, has demonstrated improved control of CINV through the full period of emetic risk with a single dose. Palonosetron is recommended as the preferred treatment of acute and delayed emesis prevention with moderate emetic risk chemotherapy in the most recently published evidence-based antiemesis consensus guidelines. Further studies incorporating dexamethasone to 5-HT(3) antagonists will be necessary to determine the relative efficacy of palonosetron compared with available agents. These trials could open a new era in the treatment of CINV.