Influenza A is a serious respiratory illness that can be debilitating and may cause complications leading to hospitalization and death. The outcome of infection with the influenza A virus is determined by a complex interplay of viral and host factors. With the ongoing threat of seasonal influenza and the potential emergence of new, more virulent strains of influenza viruses, we need to develop a better understanding of genetic variation in the human population and its association with severe outcomes from influenza infection. We propose a list of approximately 100 systems-based candidate genes for future study of the genetic basis of influenza disease and immunity in humans, based on evidence in the published literature for their potential role in the pathogenesis of this infection: binding of the virus to receptors on the host cell surface; cleavability of HA by host proteases; virus replication in host cells; destruction of host cells by apoptosis; state of immunocompetence of the individual host; and viral infections predisposing to bacterial infection.