An oral fixed combination of netupitant/palonosetron (NEPA; Akynzeo®) is available for use in the prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV). Netupitant is a highly selective neurokinin-1 receptor antagonist and palonosetron is a serotonin 5-HT3 receptor antagonist with a distinct pharmacological profile. Complete response rates during the delayed, acute and overall phases were significantly higher with single-dose netupitant 300 mg plus palonosetron 0.5 mg than with single-dose palonosetron 0.5 mg in cycle 1 of cisplatin-based highly emetogenic chemotherapy (HEC) in a phase II trial and with single-dose netupitant/palonosetron 300/0.5 mg than with single-dose palonosetron 0.5 mg in cycle 1 of anthracycline-cyclophosphamide (AC) moderately emetogenic chemotherapy (MEC) in a phase III trial; the greater efficacy of netupitant/palonosetron was maintained over repeated cycles of AC MEC in the phase III trial. In another phase III trial, netupitant/palonosetron 300/0.5 mg was effective over repeated cycles of non-AC MEC or HEC. Netupitant/palonosetron was well tolerated, with no cardiac safety concerns. The convenience of administering netupitant/palonosetron as a single dose in a fixed combination has the potential to improve adherence to CINV prevention guidelines. In conclusion, netupitant/palonosetron is an important option to consider in the prevention of acute and delayed CINV in patients receiving MEC or HEC.