Influenza viruses are constantly evolving targets. During their intracellular life cycle, influenza viruses usurp host pathways, and pandemic strains must be able to gain access to these pathways in new organisms during cross-species transmission. Therefore, uncovering the molecular basis of pandemic influenza A virus strains is central to our preparedness against pandemics. Throughout my thesis work, I have thoroughly explored the virus:host interaction network of the potentially pandemic strain H5N1 through a CRISPR genome-wide screen, identifying and characterizing host factors, including CIC as a novel regulator of cell intrinsic immunity, and defining new roles for already known host factors, including Rab11a. These findings elicit druggable host factors for influenza viruses, augmenting our potential antiviral stockpile. Moreover, this work enhances our understanding of central pillars of the immune response, broadening the scope of this research to the control of multiple viruses and potentially other disease states.