Mechanical ventilation is a life-saving intervention for patients with respiratory failure or during deep sedation. During continuous mandatory ventilation the diaphragm remains inactive, which activates pathophysiological cascades leading to a loss of contractile force and muscle mass (collectively referred to as ventilator-induced diaphragm dysfunction, VIDD). In contrast to peripheral skeletal muscles this process is rapid and develops after as little as 12 h and has a profound influence on weaning patients from mechanical ventilation as well as increased incidences of morbidity and mortality. In recent years, animal experiments have revealed pathophysiological mechanisms which have been confirmed in humans. One major mechanism is the mitochondrial generation of reactive oxygen species that have been shown to damage contractile proteins and facilitate protease activation. Besides atrophy due to inactivity, drug interactions can induce further muscle atrophy. Data from animal research concerning the influence of corticosteroids emphasize a dose-dependent influence on diaphragm atrophy and function although the clinical interpretation in intensive care patients (ICU) patients might be difficult. Levosimendan has also been proven to increase diaphragm contractile forces in humans which may prove to be helpful for patients experiencing difficult weaning. Additionally, antioxidant drugs that scavenge reactive oxygen species have been demonstrated to protect the diaphragm from VIDD in several animal studies. The translation of these drugs into the IUC setting might protect patients from VIDD and facilitate the weaning process.