Life-saving mechanical ventilation (MV) induces or exacerbates a range of pulmonary pathologies, collectively known as ventilator-induced lung injury if there is evidence of direct causation (i.e., in the research laboratory). However, in clinical practice, the term ventilator-associated lung injury (VALI) is more appropriate. While several factors are involved, the main drivers of the pathogenesis are regional overdistention and clinical atelectasis. This understanding has led to search for strategies to attenuate VALI and improve survival. The current approaches focus on reduction of lung stress and strain by limitation of alveolar–plateau pressure and tidal volume. Recent data suggest that control of driving pressure (plateau pressure–positive end-expiratory pressure) and mechanical power applied during ventilation may also be beneficial. More exciting are the various new techniques for MV (e.g., airway pressure release ventilation and neurally adjusted ventilatory assist), emerging alternative modalities for gas exchange (e.g., extracorporeal membrane oxygenation), and novel biological therapies (e.g., anti-inflammatory stem cells) that promise to revolutionize the management of respiratory failure and relegate VALI to the ash heap of history. However, there are currently insufficient data to recommend their use in routine clinical practice.