Influenza A and B viruses are RNA viruses that present neuraminidase as one of their envelope-inserted glycoproteins. These viruses, because of their complexity and high mutation rates, exhibit high prevalence among human beings and are causal agents of annual flu epidemics. They are responsible for significant morbidity and mortality and cause 250,000 to 500,000 deaths worldwide per year, especially among the elderly, children and patients presenting respiratory, renal and cardiac diseases. Through the centuries, influenza A viruses have been identified as agents of flu pandemics. During infection, the viral neuraminidase plays a critical role in the virus particles dissemination by releasing the terminal sialic acid residues on the cytoplasmatic membrane by cleaving α-2,3 and α-2,6 ketosidic linkages, which involves a chair-boat conformational change. Neuraminidase presents exo-glycohydrolase activity, exhibiting an active site that is highly conserved in nine of the antigenic neuraminidase subtypes of influenza A viruses. The neuramidase active site exhibits a central rigid catalytic structure with 19 highly conserved amino acid residues and is thus considered to be an interesting attractive target for the design of anti-influenza drugs. Zanamivir and oseltamivir, two anti-influenza neuraminidase drugs, were introduced in 1999. However, since the anti-neuraminidase drugs were introduced, the appearance of conformational changes responsible for the development of clinically relevant resistance has become a critical topic. Resistance of influenza A H1N1 viruses to oseltamivir was first observed in 2001, and the circulation of oseltamivir-resistant and zanamivir-resistant samples of influenza A (H1N1 and H3N2) and B viruses have already been observed. The most commonly reported cases of recent oseltamivirresistant viruses present a 275 mutation (H275Y) on the neuraminidase (NA) molecule, a substitution that is known to be responsible for high levels of resistance only to oseltamivir; other point mutations have been observed to confer resistance to zanamivir and peramivir. The aim of this chapter is to report the presence of mutations that induce resistance to anti-neuraminidase drugs that have been licensed by the FDA for flu treatment in the ten last years in the Americas.