Infection with influenza viruses, including seasonal, avian and pandemic viruses, remains a worldwide public health problem. Although influenza virus infection is both vaccine preventable and drug treatable, high rates of mutation and reassortment of viruses can result in reduced effectiveness of vaccines or drugs. Currently, two classes of drugs, adamantanes (M2 blockers) and neuraminidase (NA) inhibitors (NAIs), are available for treatment and chemoprophylaxis of influenza infections. Given these limited antiviral therapy options, resistance to anti-influenza drugs is a constant concern. The emergence and global spread of adamantane-resistant H3N2 viruses in 2003-2004 and oseltamivir-resistant seasonal H1N1 viruses in 2007-2009 demonstrated the ability of drug-resistant variants to rapidly become predominant worldwide. Since the 2009 H1N1 pandemic, all influenza viruses circulating in humans are M2-blocker-resistant and, in general, NAI-susceptible. However, pandemic H1N1 viruses with resistance to the NAI oseltamivir have been reported. 'Permissive' drift mutations and reassortment of viral gene segments have been proposed as mechanisms underlying the retained replicative fitness of resistant viruses. Nevertheless, the precise role of these genetic changes in the efficient transmission and maintenance of resistant viruses in the absence of drug pressure remains poorly understood. In this review, we summarize NAI resistance in influenza viruses and discuss recent challenges in laboratory testing methods. Close monitoring of antiviral resistance among all influenza viruses, both locally and globally, are essential to inform public health strategies for the control of influenza infections.