With the recognition that the 5-hydroxytryptamine receptor was important in mediating cisplatin-induced emesis, work at several pharmaceutical companies focused on creating drugs that interfered with serotonin binding utilizing a variety of medicinal chemistry strategies. The first-generation 5-hydroxytryptamine receptor antagonists (5-HT3 RAs) ondansetron, granisetron, tropisetron, and dolasetron were structurally similar and showed activity in preventing chemotherapy-induced nausea and vomiting. However, complete response during the acute phase after cisplatin was achieved in only 50–70 % of patients and was substantially less effective in the delayed phase for control of both emesis and nausea. The first-generation 5-HT3 RAs do not improve control of delayed CINV over dexamethasone alone , nor does prolonged administration provide much additional benefit . In addition, the first-generation 5-HT3 RAs were therapeutically equivalent with several large trials comparing these drugs to one another demonstrating similar efficacy [3, 4]. A plateau in 5-HT3 RA activity had been reached. Efforts persisted to find potentially more active agents based on the understanding of the central importance of this specific serotonin receptor in ameliorating chemotherapy-induced emesis.