The extracellular matrix (ECM) plays an important role in the biomechanical behaviour of the lung parenchyma. The ECM is composed of a three-dimensional fibre mesh filled with different macromolecules, including the glycosaminoglycans and the proteoglycans, which have important functions in many lung pathophysiological processes: (1) regulating the hydration and water homeostasis, (2) maintaining the structure and function, (3) modulating the inflammatory response, and (4) influencing tissue repair and remodelling. Ventilator-induced lung injury is the result of a complex interplay among various mechanical forces acting on lung structures such as the epithelial and endothelial cells, the extracellular matrix, and the peripheral airways during mechanical ventilation. Although excellent reviews have synthesized our current knowledge of the role of repeated cyclic stretch and high tidal volume ventilation on alveolar and endothelial cells, few have addressed the effects of mechanical ventilation on the ECM. The present review focused on the organization of the ECM, mechanotransduction and ECM interactions, and the effects of mechanical ventilation on the ECM. The study of the ECM may be useful to improve our understanding of the pathophysiology of lung damage induced by mechanical ventilation.