Acute lung injury, and its severe form, acute respiratory distress syndrome (ARDS), affect thousands of people per year in the US. Management of ARDS frequently involves administration of supportive mechanical ventilation. Mechanical ventilation itself, however, can make matters worse by causing ventilator-induced lung injury (VILI). Modeling plays a vital role in quantitatively defining the link between mechanical ventilation and VILI production by predicting the lung tissue damage caused by over-distension (volutrauma) and repetitive recruitment of derecruited lung units (atelectrauma). VILI can be predicted in an overall sense using a single compartment model that embodies both alveolar tissue distension and recruitment of closed lung units. VILI development can be modeled more accurately by associating a virtual trajectory with each independent lung unit. Tissue overdistention and repetitive recruitment also act synergistically, which can be explained on the basis of a rich-get-richer mechanism. Failure of the blood-gas barrier by repetitive recruitment can be explained on the basis of a multi-hit mechanism in which multiple intercellular adhesions must fail before plasma derived material starts leaking into the alveoli. Models based on these mechanisms explain how VILI develops over time during injurious mechanical ventilation and the critical role played by pulmonary surfactant dysfunction.