The clinical and experimental literature has unequivocally established that mechanical ventilation with large tidal volumes is injurious to the lung. However, uncertainty about the micromechanics of injured lungs and the numerous degrees of freedom in ventilator settings leave many unanswered questions about the biophysical determinants of lung injury. In this review we focus on experimental evidence for lung cells as injury targets and the relevance of these studies for human ventilator-associated lung injury. In vitro, the stress-induced mechanical interactions between matrix and adherent cells are important for cellular remodeling as a means for preventing compromise of cell structure and ultimately cell injury or death. In vivo, these same principles apply. Large tidal volume mechanical ventilation results in physical breaks in alveolar epithelial and endothelial plasma membrane integrity and subsequent triggering of proinflammatory signaling cascades resulting in the cytokine milieu and pathologic and physiologic findings of ventilator-associated lung injury. Importantly, though, alveolar cells possess cellular repair and remodeling mechanisms that in addition to protecting the stressed cell provide potential molecular targets for the prevention and treatment of ventilator-associated lung injury in the future.