Mechanical ventilation (MV) is an essential part of modern intensive care medicine. MV is performed in patients with severe respiratory failure caused by respiratory muscle insufficiency and/or lung parenchymal disease; that is, when other treatments such as medication, oxygen administration, secretion management, continuous positive airway pressure (CPAP), or nasal high-flow therapy have failed. MV is required for maintaining gas exchange and allows more time to curatively treat the underlying cause of respiratory failure. In the majority of ventilated patients, liberation or “weaning” from MV is routine, without the occurrence of any major problems. However, approximately 20% of patients require ongoing MV, despite amelioration of the conditions that precipitated the need for it in the first place. Approximately 40–50% of the time spent on MV is required to liberate the patient from the ventilator, a process called “weaning”. In addition to acute respiratory failure, numerous factors can influence the duration and success rate of the weaning process; these include age, comorbidities, and conditions and complications acquired during the ICU stay. According to international consensus, “prolonged weaning” is defined as the weaning process in patients who have failed at least 3 weaning attempts, or require more than 7 days of weaning after the first spontaneous breathing trial (SBT). Given that prolonged weaning is a complex process, an interdisciplinary approach is essential for it to be successful. In specialised weaning centres, approximately 50% of patients with initial weaning failure can be liberated from MV after prolonged weaning. However, the heterogeneity of patients undergoing prolonged weaning precludes the direct comparison of individual centres. Patients with persistent weaning failure either die during the weaning process, or are discharged back to their home or to a long-term care facility with ongoing MV. Urged by the growing importance of prolonged weaning, this Sk2 Guideline was first published in 2014 as an initiative of the German Respiratory Society (DGP), in conjunction with other scientific societies involved in prolonged weaning. The emergence of new research, clinical study findings and registry data, as well as the accumulation of experience in daily practice, have made the revision of this guideline necessary. The following topics are dealt with in the present guideline: Definitions, epidemiology, weaning categories, underlying pathophysiology, prevention of prolonged weaning, treatment strategies in prolonged weaning, the weaning unit, discharge from hospital on MV, and recommendations for end-of-life decisions. Special emphasis was placed on the following themes: (1) A new classification of patient sub-groups in prolonged weaning. (2) Important aspects of pulmonary rehabilitation and neurorehabilitation in prolonged weaning. (3) Infrastructure and process organisation in the care of patients in prolonged weaning based on a continuous treatment concept. (4) Changes in therapeutic goals and communication with relatives. Aspects of paediatric weaning are addressed separately within individual chapters. The main aim of the revised guideline was to summarize both current evidence and expert-based knowledge on the topic of “prolonged weaning”, and to use this information as a foundation for formulating recommendations related to “prolonged weaning”, not only in acute medicine but also in the field of chronic intensive care medicine. The following professionals served as important addressees for this guideline: intensivists, pulmonary medicine specialists, anaesthesiologists, internists, cardiologists, surgeons, neurologists, paediatricians, geriatricians, palliative care clinicians, rehabilitation physicians, intensive/chronic care nurses, physiotherapists, respiratory therapists, speech therapists, medical service of health insurance, and associated ventilator manufacturers.