Virus–cell fusion is the key step for viral infection in host cells. Studies on virus binding and fusion with host cells are important for understanding the virus–host interaction and viral path-ogenesis for the discovery of antiviral drugs. In this review, we focus on the virus–cell fusions induced by the two major pandemic viruses, including the influenza virus and SARS-CoV-2. We fur-ther compare the cell fusions induced by the influenza virus and SARS-CoV-2, especially the pH-dependent fusion of the influenza virus and the fusion of SARS-CoV-2 in the type-II transmembrane serine protease 2 negative (TMPRSS2) cells with syncytia formation. Finally, we present the development of drugs used against SARA-CoV-2 and the influenza virus through the discovery of anti-fusion drugs and the prevention of pandemic respiratory viruses.