Influenza viruses are classified as A, B, or C based on the antigenicity of their nucleoproteins and matrix proteins. Influenza A viruses are further categorized into subtypes based on the antigenicity of two of their surface proteins, the hemagglutinin and neuraminidase. All avian influenza viruses are type A viruses. While the majority of avian influenza viruses are avirulent, viruses of a limited number of subtypes cause severe disease in birds. This difference in pathogenicity among avian influenza viruses is primarily determined by the amino acid sequence at the viral hemagglutinin cleavage site. Since 1997, there have been multiple reports of human infection by highly pathogenic avian influenza viruses. Acquisition of the ability to cause human-to-human transmission by avian influenza viruses will confront the human population with an influenza pandemic crisis. Here we review the molecular basis of pathogenicity of avian influenza viruses in humans.