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Influenza viruses are major human pathogens with a global distribution, accounting for more than 500,000 annual deaths worldwide and with considerable impact on the quality of life and productivity of the society. Due to the limited efficacy of vaccination, antiviral drugs constitute a complementary approach in the control and prevention of influenza infections and thus play an important role in the management of influenza outbreaks and pandemics. Currently, adamantanes and neuraminidase inhibitors (NAIs) are the only two classes of anti-influenza agents approved for clinical use. However, the worldwide emergence and high prevalence of adamantane-resistant virus variants has discouraged the use of the former drugs. NAIs have proved to be very effective against influenza A and B viruses. Nevertheless, oseltamivir-resistant strains have also been reported quite frequently, as in the case of seasonal H1N1 viruses that circulated between 2007 and 2009. Indeed, the emergence of drug-resistant virus variants is always a matter of concern because it could significantly compromise the usefulness of such intervention. This highlights the need for continuous monitoring of resistance markers, as well as the development of new anti-influenza drugs and combination therapies.