Influenza is a global challenge, and future pandemics of influenza are inevitable. One of the lessons learned from past pandemics is that all pandemic influenza viruses characterized to date possess viral genes originating from avian influenza viruses (AIVs). During the past decades, a wide range of AIVs have overcome the species barrier and infected humans with different clinical manifestations ranging from mild illness to severe disease and even death. Understanding the mechanisms of infection in the context of clinical outcomes, the mechanism of interspecies transmission, and the molecular determinants that confer interspecies transmission is important for pandemic preparedness. Here, we summarize the epidemiology, virology, and pathogenicity of human infections with AIVs to further our understanding of interspecies transmission.