Understanding and controlling the activation of innate antiviral immune responses is an important step toward novel therapies. About a fifth of world's population is infected by IAV annually, leading to high morbidity and mortality, particularly in infants, the elderly and the immunocompromised. The high mutation rate of IAV turns all attempts of vaccine and antiviral design into a never ending battle. In recent years, RNA interference, triggered by synthetic short interfering RNA (siRNA), has rapidly evolved as a potent antiviral regimen. Properly designed siRNAs have been shown to function as potent inhibitors of influenza virus replication. Although specificity and tissue delivery remain major bottlenecks in the clinical applications of RNAi in general, intranasal application of siRNA against respiratory viruses including, but not limited to influenza virus, has experienced significant success and optimism [83]. Our results suggest that not only siRNA targeting IAV components, but boosting the antiviral immune response by intranasal administration of siRNA against A20 might be a valid therapeutic approach. Also small compound inhibitors of A20 might be an interesting alternative. Finally, similar targeting of A20 might be of interest in the battle against other viral infections including RSV and SARS coronavirus.