Proteolytic cleavage of the influenza virus hemagglutinin glycoprotein (HA) by cellular proteases is a prerequisite for virus infectivity, spread of the virus in the infected organism, tissue tropism, and viral pathogenicity. Production of infectious virus depends upon the structure at the HA cleavage site as well as the substrate specificity and the distribution of appropriate enzymes. Differences exist in the specificities of the endoproteases that recognize the different sequence motifs at the cleavage site. With avian influenza viruses that cause lethal systemic infections, the cleavage site consists of multi-basic amino acids. Furin, which activates this type of HA, is a member of the subtilisin family and represents the prototype of ubiquitously occurring membrane-bound proteases. On the other hand, serine proteases secreted from a restricted number of cell types and some bacterial enzymes recognize a monobasic cleavage signal at HA of the mammalian and the apathogenic avian influenza viruses. The limited occurrence of these proteases results in only localized infection. Implementation of these defined conditions for virus activation may represent a novel type of disease control. Rott R, Klenk H-D, Nagai Y, Tashiro M. Influenza viruses, cell enzymes, and pathogenicity.