The efficacy of current influenza antiviral drugs is compromised by emerging drug resistance. To address this unmet medical need, we have made progress in developing novel influenza antivirals by targeting the drug-resistant mutants of M2 and the viral polymerase. In this presentation, I will introduce our work in designing inhibitors targeting the viral M2-S31N mutant proton channel and the viral polymerase PA-PB1 interactions. The designed M2-S31N inhibitors and the PA-PB1 inhibitors have been shown to inhibit drug resistant influenza viruses with potent antiviral efficacy and a high selectivity index.