Pandemics of influenza have been reported since the early sixteenth century. Recent pandemics include the Spanish flu (H1N1) from 1918 to 1920 (resulting in approximately 50 million deaths worldwide); the Asian flu (H2N2) from 1957 to 1958 (resulting in more than 1 million deaths); the Hong Kong flu (H3N2) from 1968 to 1970 (responsible for approximately 700,000 deaths). Avian influenza viruses have now been identified as a source of novel hemagglutinin (HA) and neuraminidases (NAs) associated with pandemics. Although infections in humans with avian strains are uncommon, several outbreaks of severe influenza with highly virulent H5N1 strains derived from infected poultry were reported in China and other Asian countries since 2003. Large-scale culling operations and intensified surveillance led to eradication of H5N1 infection in poultry in some countries, but H5N1 infection in wild birds and domestic poultry has become endemic in many countries. The potential exists for global pandemics of unprecedented magnitude. In this review, we discuss the epidemiology and genetics of avian influenza viruses, the potential for transmission of disease to humans, clinical features of avian influenza infections in humans, appropriate diagnostic testing, and treatment. We also discuss global efforts for disease prevention via a host of programs, including intensified surveillance, culling of infected birds, education of medical personnel and the public, production of vaccines, and use of specific antiviral agents (e.g., adamantanes and neuraminidase inhibitors).