Neutrophils are an important component of the inflammatory response that characterizes acute lung injury (ALI). This discussion aims to review the contribution of neutrophils to the development and progression of ALI and to highlight the major intracellular signaling pathways that are involved in neutrophil activation in the setting of ALI. MEDLINE, original research papers, and review papers. Relevant laboratory and clinical studies. Systemic review. Activated neutrophils appear to play a central role in the development of most cases of ALI. In experimental models, the elimination of neutrophils markedly decreases the severity of ALI. Furthermore, in neutropenic patients with lung injury, deterioration of pulmonary function as neutropenia resolves has been well described. The neutrophils that accumulate in the lungs in models of ALI demonstrate increased activation of the kinases Akt and p38; increased nuclear accumulation of the transcriptional regulatory factor, nuclear factor-kappaB; and increased production of proinflammatory cytokines, particularly those whose transcription is dependent on nuclear factor-kappaB. Decreased apoptosis among neutrophils in the lungs is also characteristic. Inhibiting p38, Akt, or nuclear factor-kappaB activation diminishes the severity of endotoxin- or hemorrhage-induced ALI. The accumulation of activated neutrophils in the lungs is an early step in the pulmonary inflammatory process that leads to ALI. Although experimental models indicate that the activation of p38, Akt, and nuclear factor-kappaB in neutrophils contributes to ALI, the relative importance of these pathways in critically ill patients remains to be determined. Nevertheless, modulation of the activation of p38, Akt, and nuclear factor-kappaB in neutrophils appears to be an appropriate therapeutic target in severely ill patients with ALI.