Mechanical ventilation can be lifesaving, but may initiate and perpetuate ventilator-induced lung injury. This has many manifestations, from pneumothorax to multi-system organ failure. Although the precise underlying mechanisms have not yet been elucidated, various signalling pathways are thought to be involved and shall be discussed in this review. A key component in the pathogenesis of lung injury is biotrauma, comprising a triggering of intracellular signalling pathways to upregulate inflammatory processes in response to alveolar membrane deformation. This mechanotransduction arises from a possible combination of at least three mechanisms: Activation of stretch-sensitive alveolar membrane ion channels, plasma membrane disruption causing a wave of calcium release and/or integrin activation producing cytoskeletal rearrangement. The consequence is increased expression of c-fos and Nuclear Factor-κB, important regulators of the inflammatory response. Since an understanding of the signalling cascades involved will help to design strategies to diminish the immune response, this review also highlights the implications for therapies to minimise lung damage in the clinical setting, such as the use of anti-TNF-α -antibody. There is obviously much scope for future research in this area, and perhaps further investigation into components of the cascades will reveal potential targets for therapeutic interventions? In this way, the mortality of ventilated patients may be reduced.