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The adult respiratory distress syndrome (ARDS) is a common cause of respiratory failure with substantial impact on public health. Patients with ARDS generally require mechanical ventilation, which risks further lung damage. Recent improvements in ARDS outcomes have been attributed to reductions in deforming stress associated with lung protective mechanical ventilation modes and settings. The following review details the mechanics of the lung parenchyma at different spatial scales and the response of its resident cells to deforming stress in order to provide the biologic underpinnings of lung protective care.Although lung injury is typically viewed through the lens of altered barrier properties and mechanical ventilation-associated immune responses, in this review, we call attention to the importance of heterogeneity and the physical failure of the load bearing cell and tissue elements in the pathogenesis of ARDS. Specifically, we introduce a simple elastic network model to better understand the deformations of lung regions, intra-acinar alveoli and cells within a single alveolus, and consider the role of regional distension and interfacial stress-related injury for various ventilation modes.Heterogeneity of stiffness and intercellular and intracellular stress failure are fundamental components of ARDS and their development also depends on the ventilation mode.