Since their emergence as avian (1996) and zoonotic human pathogens (1997), H5N1 influenza viruses have become endemic among poultry in large parts of Asia, but outbreaks have also been seen in Africa and Europe. Transmission from animals to humans remains sporadic, but mortality of human infection is high (63%). To date, reported cases of human to human transmission have been rare. Patient and laboratory data suggest that highly efficient viral replication and the resulting intensified immune response of the human host are the determining factors in H5N1 pathogenesis and case fatality rate. Therefore, in the management of H5N1 disease (early) suppression of viral replication is key. The underlying biochemistry and cell biology of H5N1 pathogenesis and treatment are briefly discussed in this review.