It is an accepted concept that the pathogenicity of a virus is of polygenic nature. Because of their segmented genome, influenza viruses provide a suitable system to prove this concept. The studies employing virus mutants and reassortants have indicated that the pathogenicity depends on the functional integrity of each gene and on a gene constellation optimal for the infection of a given host. As a consequence, virtually every gene product of influenza virus has been reported to contribute to pathogenicity, but evidence is steadily growing that a key role has to be assigned to hemagglutinin. As the initiator of infection, hemagglutinin has a double function: (1) promotion of adsorption of the virus to the cell surface, and (2) penetration of the viral genome through a fusion process among viral and cellular membranes. Adsorption is based on the binding to neuraminic acid-containing receptors, and different virus strains display a distinct preference for specific oligosaccharides. Fusion capacity depends on proteolytic cleavage by host proteases, and variations in amino acid sequence at the cleavage site determine whether hemagglutinin is activated in a given cell. Differences in cleavability and presumably also in receptor specificity are important determinants for host tropism, spread of infection, and pathogenicity. The concept that proteolytic activation is a determinant for pathogenicity was originally derived from studies on avian influenza viruses, but there is now evidence that it may also be relevant for the disease in humans because bacterial proteases have been found to promote the development of influenza pneumonia in mammals.