The prevention of chemotherapy-induced nausea and vomiting (CINV) has improved significantly with the introduction of the 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists combined with dexamethasone. Most studies have reported on patients undergoing single-day highly or moderately emetogenic chemotherapy. There have been fewer studies and much less success in preventing CINV in patients undergoing multiple-day chemotherapy or high-dose chemotherapy with stem cell transplant. Current practice guidelines suggest the use of a first-generation 5-HT3 receptor antagonist and dexamethasone daily for each day of the multiple-day chemotherapy regimens. This practice seems to control acute CINV, but delayed CINV remains poorly controlled with a complete response (e.g., no emesis, no rescue) of less than 50% in most studies. Three new agents - palonosetron, aprepitant, and olanzapine - have shown high efficacy in preventing acute and delayed CINV in patients undergoing single-day chemotherapy. These agents have high potential for preventing CINV in patients undergoing multiple-day chemotherapy. This article proposes recommendations for their use in clinical trials and in practice. © Journal of the National Comprehensive Cancer Network.