Macrophages are key defenders of the lung and play an essential role in mediating the inflammatory response. Critical to this is the activation of the NADPH oxidase. Through receptor-mediated interactions, extracellular stimuli activate pathways that signal for the phosphorylation and assembly of the NADPH oxidase. Once the NADPH oxidase is activated, it produces superoxide and H 2O 2 in a process known as the respiratory burst. The involvement of O 2.- and H 2O 2 in the antimicrobicidal function of macrophages has been assumed for many years, but it is now clear that the H 2O 2 produced by the respiratory burst functions as a second messenger and activates major signaling pathways in the alveolar macrophage. Both the nuclear factor-κB and activator protein-1 transcription factors are activated by H 2O 2 produced by the respiratory burst, and, since these control the inducible expression of genes whose products are part of the inflammatory response, this may be a critical link between the respiratory burst and other inflammatory responses. The c-Jun N-terminal kinase (JNK) and extracellular-regulated kinase (ERK) pathways, two members of the mitogen-activated protein kinase family, are also activated by the respiratory burst. JNK is activated by both exogenous and endogenously produced H 2O 2. Studies with ERK have shown that specific agonists of the respiratory burst, but not bolus H 2O 2, can activate this pathway. The ERK pathway also modulates the expression of genes via phosphorylation of the transcription factor Elk-1 that controls the production of the c-Fos transcription factor. Although an understanding of the mechanism of redox signaling is in its infancy, it is becoming clear that the reactive oxygen species produced by the respiratory burst have a profound effect on intracellular signaling pathways and ultimately in modulating gene expression.