Innate immune responses to lung pathogens involve the coordinated expression of myriad affector and effector molecules of innate immunity, which must be induced and appropriately regulated in response to diverse stimuli generated by microbes or the infected host. Many intercellular and intracellular signaling pathways are involved, but we propose NF-κB and STAT3 transcription factors to be especially important signaling hubs for integrating these pathways to orchestrate effective host defense without excessive inflammatory injury.