Ventilator-induced lung injury (VILI) consists of tissue damage and a biological response resulting from the application of inappropriate mechanical forces to the lung parenchyma. The current paradigm attributes VILI to overstretching due to very high-volume ventilation (volutrauma) and cyclic changes in aeration due to very low-volume ventilation (atelectrauma); however, this model cannot explain some research findings. In the present review, we discuss the relevance of cyclic deformation of lung tissue as the main determinant of VILI. Parenchymal stability resulting from the interplay of respiratory parameters such as tidal volume, positive end-expiratory pressure or respiratory rate can explain the results of different clinical trials and experimental studies that do not fit with the classic volutrauma/atelectrauma model. Focusing on tissue deformation could lead to new bedside monitoring and ventilatory strategies.