Influenza is one of the most common infectious diseases in humans occurring as seasonal epidemic and sporadic pandemic outbreaks. The ongoing infections of humans with avian H5N1 influenza A viruses (IAV) and the past 2009 pandemic caused by the quadruple human/avian/swine reassortant (H1N1) virus highlights the permanent threat caused by these viruses. This review aims to describe the interaction between the virus and the host, with a particular focus on the role of proteases and HLA-G in the pathogenicity of influenza viruses.