Here we have employed the cytopathic effects of H1N1 infection in bronchial epithelial cells as a mechanism to isolate host genes that represent intervention target opportunities by virtue of their contribution to H1N1 infection and replication, or by virtue of their contribution to viral virulence factor-dependent evasion of innate immune responses. A primary whole-genome arrayed siRNA screen identified gene depletions that either deflected or promoted bronchial epithelial cell death upon exposure to the H1N1 A/WSN/33 influenza virus and were not cytotoxic to mock infected cells. Integration with orthogonal data sets, describing host gene function [4] [5] [6] [7] [8] , parsed collective 'targets' into four functional classes. 1) Targets that, when depleted, enhance bronchial epithelial cell survival upon H1N1 exposure, and are required for viral replication. This class presumably represents host factors that facilitate viral infection and/or are required to support viral replication. 2) Targets that, when depleted, reduce bronchial epithelial cell survival upon H1N1 exposure, and are required for viral replication. This important and initially unanticipated class, likely represents proviral host factors that deflect cell death checkpoint responses that would otherwise engage upon detection of viral infection. 3) Targets that, when depleted, reduce bronchial epithelial cell survival upon H1N1 exposure and enhance viral replication relative to controls. Recently discovered innate immune pathway components, such as IFITM3 that are responsive to H1N1 infection, are members of this class, which presumably represent antiviral restriction factors that normally oppose infection. 4) Targets, that when depleted, enhance bronchial epithelial cell survival upon H1N1 exposure and enhance viral replication as compared to controls. These host factors are likely responsible for influenza virus-mediated cytopathic effects. Chemical inhibition of gene products from two classes, RABGGTASE and CHEK1, indicated these targets might be pharmacologically addressable for H1N1 intervention in an epithelial cell autonomous context.