Mechanical ventilation (MV) and oxygen therapy (hyperoxia; HO) comprise the cornerstones of life-saving interventions for patients with Acute Respiratory Distress Syndrome (ARDS). Unfortunately, the side effects of MV and HO include exacerbation of lung injury by barotrauma, volutrauma and propagation of lung inflammation. Despite significant improvements in ventilator technologies and a heightened awareness of oxygen toxicity, besides low tidal volume ventilation few if any medical interventions have improved ARDS outcomes over the past two decades. We are lacking a comprehensive understanding of mechano-transduction processes in the healthy lung and know little about the interactions between simultaneously activated stretch-, HO- and cytokine-induced signaling cascades in ARDS. Nevertheless, as we are unraveling these mechanisms we are gathering increasing evidence for the importance of stretch-activated ion channels (SACs) in the activation of lung resident and inflammatory cells. In addition to the discovery of new SAC families in the lung, e.g. 2-pore domain potassium (K2P) channels, we are increasingly assigning mechano-sensing properties to already known Na+, Ca2+, K+, and Cl- channels. Better insights into the mechano-transduction mechanisms of SACs will improve our understanding of the pathways leading to ventilator-induced lung injury and lead to much needed novel therapeutic approaches against ARDS by specifically targeting SACs. This review (1) summarizes the reasons why the time has come to seriously consider SACs as new therapeutic targets against ARDS, (2) critically analyzes the physiological and experimental factors that currently limit our knowledge about SACs, and (3) outlines the most important questions future research studies need to address.