As a major pathogen of human and certain animal species, influenza virus causes wide spread and potentially devastating disease. To initiate infection, the virus first binds to cellular receptors comprising either -(2,3 ) or -(2,6) linked sialic acid. Recent advances in our understanding of the influenza virus receptor and viral host species involved have shed light on the molecular mechanism of how influenza virus transmits across species and adapts to a new host. Following receptor binding, influenza viruses are internalized through multiple endocytic pathways, including both clathrin- and non-clathrin-dependent routes, which have recently been visualized at single viral particle level. The viral envelope then fuses with the endosomal membrane in a low pH-dependent manner and the viral genome is released into the cytosol, followed by further transport to the nucleus where genome replication occurs.