Long-term mechanical ventilation implies a significant number of weaning failures. The basis of this unweanability is chronic fatigue of the inspiratory muscles which is due to depletion of energy store (e.g. glycogen). Considering this pathophysiological principle, the decisive therapeutic option during weaning from long-term mechanical ventilation consists of resting the respiratory muscles. The commonly used assisted ventilation modes only partially relieve the respiratory muscles because the work of breathing is done both during the trigger phase and during the inspiratory cycle. The essential characteristic of our weaning concept includes the repeated determination of the spontaneous breathing frequency in awake patients, which is followed by controlled intermittent positive pressure ventilation with a slightly higher respiratory rate. Ideally, this results in total suppression of the activity of the breathing centre, and in subsequent relief and recovery of the respiratory muscles by replenishing the energy stores. The close succession of relief and training periods avoids inactivity-induced atrophy of the respiratory muscles and permits regeneration. Additionally, our weaning concept avoids increases in inspiratory work during the phases of spontaneous breathing. This means that high-resistance small-caliber endotracheal tubes have to be replaced by large tubes. Moreover, transtracheal oxygen insufflation during spontaneous breathing decreases anatomic dead space. This reduces minute ventilation and, therefore, the work of breathing. In patients still exhibiting chronic fatigue of the respiratory muscle pump after successful weaning, intermittent home ventilation is initiated via a breathing mask. Apart from the concept described above, successful weaning from the respirator after long-term ventilation is based upon dedicated patient care and depends on the architectural characteristics of the intensive care unit.