A wide use of inhibitors of influenza virus neuraminidase (NAIs) to control influenza in humans demands a better understanding of the mechanisms involved in the resistance emergence. In vitro studies demonstrate that both neuraminidase (NA) and hemagglutinin (HA) influence virus susceptibility to NAIs. Drug resistance conferred due to changes in the NA could be monitored in the NA inhibition assays. Zanamivir-selected viruses acquired the NA substitutions at residues 119 and 292; oseltamivir-selected--at 274 and 292; peramivir-selected--at 292; and A-315675-selected--at 119. The HA binding efficiency and therefore susceptibility to NAIs are affected by the amino acids forming the HA receptor-binding site, the location and number of oligosaccharide chains, and structure of the neuraminic acid-containing cellular receptors. The lack of suitable cell culture-based assays hampers the assessment of virus susceptibility in humans. Emergence of the viruses with the NAI-induced substitutions in the NA is uncommon in drug-treated humans, however a compromised state of the immune system promotes emergence of drug resistance. In vivo, the zanamivir-selected mutant contained a substitution at 152 (B/NA); the oseltamivir-selected mutants-at residues 119 (A/N2), 198 (B/NA), 274 (A/N1), and 292 (A/N2). Substitutions in the NA were often accompanied by impairment of virus infectivity and virulence in animal models. Because of complexity of mechanisms of virus resistance, further analysis of the viruses recovered from the drug-treated humans is warranted.