The most foolproof way to promote survival in epidemics of potentially lethal influenza is to target, not highly mutable viral proteins, but rather intracellular signaling pathways which promote viral propagation or lung inflammation. NF-kappaB, activated in influenza-infected lung epithelial cells and macrophages, is one likely target in this regard, as it plays a role both in viral replication and in the excessive lung inflammation often evoked by influenza infection. Indeed, salicylates, which suppress NF-kappaB activation, have been shown to reduce the lethality of H5N1 avian-type influenza in mice. Another potential target is NADPH oxidase, as this may be a major source of influenza-evoked oxidant stress in lung epithelial cells as well as in phagocytes attracted to lung parenchyma. A number of studies demonstrate that oxidant stress contributes to overexuberant lung inflammation and lethality in influenza-infected mice. The documented utility of N-acetylcysteine, a glutathione precursor, for promoting survival in influenza-infected mice, and diminishing the severity of influenza-like infections in elderly humans, presumably reflects a key role for oxidative stress in influenza. The lethality of influenza is also reduced in mice pretreated with adenovirus carrying the gene for heme oxygenase-1; this benefit may be mediated, at least in part, by the ability of bilirubin to inhibit NADPH oxidase. It may be feasible to replicate this benefit clinically by administering biliverdin or its homolog phycocyanobilin, richly supplied by spirulina. If this latter speculation can be confirmed in rodent studies, a practical and inexpensive regimen consisting of high-dose salicylates, spirulina, and N-acetylcysteine, initiated at the earliest feasible time, may prove to have life-saving efficacy when the next killer influenza pandemic strikes.