Since their introduction, 5-HT3 receptor antagonists have become the agents of choice in the prevention of acute chemotherapy-induced nausea and vomitting and are generally superior to high-dose metoclopramide regimens. The availability of four different agents (ondansetron, granisetron, dolasetron, and tropisetron) within this class has prompted investigations into potential differences between the drugs, which appear to be few. More importantly, the results of recently conducted randomized comparative trials in patients receiving moderately or highly emetogenic chemotherapy have demonstrated similar efficacy. Although study designs and patient populations differed, seven large comparative trials in patients receiving highly emetogenic chemotherapy reported no significant differences in complete or complete plus major response rates among the agents. Similar results were generally reported in trials evaluating patients receiving moderately emetogenic chemotherapy. The safety and tolerability of these agents also appear to be similar. The most common adverse events include headache, gastrointestinal effects, lightheadedness, and sedation. All agents are available in both intravenous and oral dosage forms and may be administered as a single dose.