The struggle between respiratory viruses and their hosts rages on. Any doubt of the importance of that battle is quickly quelled by the recent pandemic of swine flu attributable to H1N1-type influenza A virus (IAV), as well as the devastating outbreaks of avian flu (attributable to H5N1-type IAV) and severe acute respiratory syndrome (SARS)(attributable to SARS–corona virus). In addition to the viral influence on acute illness, we (and others) have presented a considerable amount of experimental evidence that respiratory viruses are responsible, at least in part, for the pathogenesis of chronic obstructive lung diseases such as asthma and chronic obstructive pulmonary disorder (1). In each instance, the severity of infection and the consequent impact of the virus on the host is likely dictated by the outcome of the chess game between the pathogen and the immune response. Thus, an understanding of the innate and adaptive immune responses to viruses (particularly respiratory viruses) remains an important public health issue, and one that can be addressed experimentally. In that regard, the article by Senft and colleagues in the April 2010 issue of the AJRCMB demonstrates once again how a common respiratory virus can resource its small genome to outwit the larger and more complex genomic repertoire of its human host (2). In particular, that report provides new evidence for how respiratory syncytial virus (RSV) can subvert the antiviral IFN signaling system in lung macrophages. The findings provide a timely opportunity to update in brief the critical roles of IFN signaling as well as cells of the innate immune system in the virus-versus-host struggle, and to describe how this information might translate into improvements in host defense and disease outcome.