The H5N1 subtype is a highly pathogenic avian influenza virus currently circulating in birds in parts of Asia and northeast Africa, which has caused fatal human infections since 1997. Continuous circulation of the virus in endemic areas has allowed genetically diverse viruses to emerge, increasing the risk of H5N1 human infection. Although human infections with H5N1 have to date been limited, experimental evidence of the aerosol transmission of mutated viruses in a mammalian infection model has revealed the pandemic potential of H5N1 virus. One of the most important viral factors for host-adaptation of influenza virus is hemagglutinin (HA), which is the principal antigen on the viral surface and is responsible for viral binding to host receptors as well as endosomal membrane fusion. Our recent reports suggest that a fine balance of the HA properties, including receptor binding specificity and pH stability, is crucial for replication in human respiratory epithelia. This review provides an overview of current knowledge on the host-adaptive mechanism of H5N1 virus HA.