Influenza A virus remains a major public health concern, both in its annual toll in death and debilitation and its potential to cause devastating pandemics. Like any other virus, influenza A viruses are strongly dependent on cellular factors for replication. One of the hallmark signaling factors activated by viral pathogens is the transcription factor NF-kappaB. Activation of NF-kappaB leads to the up-regulation of a variety of antiviral genes. Thus, the factor is commonly regarded as a major regulator of the innate immune defense to infection. However, several recent studies indicate that influenza viruses have acquired the capability to reprogram this antiviral activity and to exploit the factor for efficient replication. These data provide novel insights into the pathophysiological function of NF-kappaB in the special environment of a virus-infected cell. Furthermore, the unexpected viral dependency on a cellular signaling factor may pave the path for novel antiviral approaches targeting essential cellular components rather than viral factors.