The mechanical forces that are applied to the lungs of patients with acute lung injury during mechanical ventilation exceed those during normal ventilation at least by a factor of two (S. Uhlig & U. Uhlig TIPS 2004; 25:592-600). Many studies suggest that the overstretching of avleolar units during ventilation can lead to the activation of the innate immune system. As mechanosensors for pulmonary stretch recent work implicates ion channels, integrin receptors and caveolae. Subsequent to the initial mechanotransduction, activation of well known pro-inflammatory transcription factors such as NF-kB and MAP kinases leads to activation of pro-inflammatory genes. Gene array analysis of ventilator-induced gene induction reveals many overlapping genes compared to endotoxin-induced gene expression, among them MIP-2, TNF, IP-10 and Fas-ligand. These mediators induce local (lung) and systemic inflammation and may thus lead to acute lung injury and multiple organ failure.