Influenza viruses undergo rapid antigenic evolution and reassortment, resulting in annual epidemics and the occasional pandemics. Exposure to influenza virus hemagglutinin (HA) and neuraminidase (NA) antigen, either through vaccination or infection, induces an antibody response able to recognize only the homologous antigenic subtype. However, atypical antibody responses recognizing non-homologous influenza subtypes have been reported during infection and vaccination. Here, we review the incidence of these phenomena in published literature and discuss the potential mechanisms underlying them.