Influenza constitutes one of the most important upper respiratory tract infections regarding morbidity, and mortality. Prevention and treatment of influenza rely on inactivated vaccines and antiviral drugs. Zanamivir and Oseltamivir, the currently available influenza neuraminidase inhibitors (NAI) can be used in clinical practice for the treatment of influenza infection. These drugs have also shown their efficacy against highly pathogenic avian influenza. Recent transmission of avian H7N7 and H5N1 influenza virus to human emphasized the need for active antiviral against emerging influenza viruses. Since their introduction in clinical practice, numerous studies have been implemented to determine the rate of emergence of NAI resistant isolates. These studies describe mechanisms of resistance associated to mutations in the neuraminidase protein, and their consequence in virus fitness and transmission. This review is summarizing the mutations described in human and avian influenza neuraminidases that are associated to resistance or reduction in sensitivity.