Mechanical ventilation is life-saving for patients with acute respiratory insufficiency. In a German prevalence study, 13.6% of patients in intensive care units received mechanical ventilation for more than 12 hours; 20% of these patients received mechanical ventilation as treatment for acute respiratory distress syndrome (ARDS). The new S3 guideline is the first to contain recommendations for the entire process of treatment in these groups of patients (indications, ventilation modes/parameters, accompanying measures, treatments for refractory impairment of gas exchange, weaning, and follow-up care). This guideline was developed according to the GRADE methods. Pertinent publications were identified by a systematic search of the literature, the quality of the evidence was evaluated, a risk/benefit assessment was conducted, and recommendations were issued by interdisciplinary consensus. Mechanical ventilation is recommended as primary treatment for patients with severe ARDS. In other patient groups, non-invasive ventilation can lower mortality. If mechanical ventilation is needed, ventilation modes allowing spontaneous breathing seem beneficial (quality of evidence [QoE]: very low). Protective ventilation (high positive end-expiratory pressure, low tidal volume, limited peak pressure) improve the survival of ARDS patients (QoE: high). If a severe impairment of gas exchange is present, prone positioning lessens mortality (QoE: high). Veno-venous extracorporeal membrane oxygenation (vvECMO) has not unequivocally been shown to improve survival. Early mobilization and weaning protocols can shorten the duration of ventilation (QoE: moderate). Recommendations for patients undergoing mechanical ventilation include lung-protective ventilation, early spontaneous breathing and mobilization, weaning protocols, and, for those with severe impairment of gas exchange, prone positioning. It is further recommended that patients with ARDS and refractory impairment of gas exchange should be transferred to an ARDS/ECMO center, where extracorporeal methods should be applied only after application of all other therapeutic options.