Introduction: The emergence of drug-resistant influenza virus strains highlights the need for new antiviral therapeutics to combat future pandemic outbreaks as well as continuing seasonal cycles of influenza.

Areas covered: This review summarizes the mechanisms of current FDA-approved anti-influenza drugs and patterns of resistance to those drugs. It also discusses potential novel targets for broad-spectrum antiviral drugs and recent progress in novel drug design to overcome drug resistance in influenza.

Expert opinion: Using the available structural information about drug-binding pockets, research is currently underway to identify molecular interactions that can be exploited to generate new antiviral drugs. Despite continued efforts, antivirals targeting viral surface proteins like HA, NA, and M2, are all susceptible to developing resistance. Structural information on the internal viral polymerase complex (PB1, PB2, and PA) provides a new avenue for influenza drug discovery. Host factors, either at the initial step of viral infection or at the later step of nuclear trafficking of viral RNP complex, are being actively pursued to generate novel drugs with new modes of action, without resulting in drug resistance.