The Southeast Asian outbreak of the highly lethal avian influenza A H5N1 infection in humans is unlikely to abate because of the enormous number of backyard farms providing poultry as the main source of food protein in developing countries. This increases the risk of the emergence of a reassortant pandemic influenza virus with improved human-to-human transmissibility. Currently triage of suspected cases by epidemiological risk factors remains the only practical way of case identification for laboratory investigation and infection control. The clinical usefulness of rapid diagnostic laboratory tests requires more vigorous evaluation. The lethality of this disease may reflect systemic viral dissemination, cytokine storm, or alveolar flooding due to inhibition of cellular sodium channels. The present circulating genotype Z is intrinsically resistant to amantadine and rimantadine. Prognosis may be improved by early treatment with a neuraminidase inhibitor with good systemic drug levels, and post-exposure prophylaxis for health care workers is recommended. The role of immunomodulators and other modalities of therapy requires evaluation in randomised controlled trials, with prospective monitoring of the viral load and cytokine profiles in various clinical specimens. In view of the high fatality of the disease, a combination of contact, droplet, and airborne precautions are recommended as long as resources allow despite the fact that the relative importance of these three modes in nosocomial transmission of avian influenza is still unknown.