Influenza virus epidemics are caused when seasonal influenza viruses (i.e., those circulating in humans) acquire mutations in the antigenic sites of the viral hemagglutinin (HA) protein that prevent the antibodies present in people from binding to the virus and blocking virus interaction with cellular receptors. To date, vaccination is the best protective option against seasonal influenza viruses. Because influenza viruses frequently acquire mutations in their antigenic sites, vaccine viruses need to be updated regularly. Here, we present an experimental system that allows the simulation of influenza virus evolution in the test tube. By using this system, we can identify antigenic variants that may emerge among natural influenza viruses in the near future. This information would help in the selection and prioritization of variants for vaccine production.