Avian influenza virus can cause serious disease in a wide variety of birds and mammals, but its natural host range is in wild ducks, gulls, and shorebirds. Infections in poultry can be inapparent or cause respiratory disease, decreases in production, or a rapidly fatal systemic disease known as highly pathogenic avian influenza (HPAI). For the protection of poultry, neutralizing antibody to the hemagglutinin and neuraminidase proteins provide the primary protection against disease. A variety of vaccines elicit neutralizing antibody, including killed whole virus vaccines and fowl-pox recombinant vaccines. Antigenic drift of influenza viruses appears to be less important in causing vaccine failures in poultry as compared to humans. The cytotoxic T lymphocyte response can reduce viral shedding in mildly pathogenic avian influenza viruses, but provides questionable protection against HPAI. Influenza viruses can directly affect the immune response of infected birds, and the role of the Mx gene, interferons, and other cytokines in protection from disease remains unknown.