Intrinsic positive end-expiratory pressure (auto-PEEP) is a common occurrence in patients with acute respiratory failure requiring mechanical ventilation. Auto-PEEP can cause severe respiratory and hemodynamic compromise. The presence of auto-PEEP should be suspected when airflow at end-exhalation is not zero. In patients receiving controlled mechanical ventilation, auto-PEEP can be estimated measuring the rise in airway pressure during an end-expiratory occlusion maneuver. In patients who trigger the ventilator or who are not connected to a ventilator, auto-PEEP can be estimated by simultaneous recordings of airflow and airway and esophageal pressure, respectively. The best technique to accurately measure auto-PEEP in patients who actively recruit their expiratory muscle remains controversial. Strategies that may reduce auto-PEEP include reduction of minute ventilation, use of small tidal volumes and prolongation of the time available for exhalation. In patients in whom auto-PEEP is caused by expiratory flow limitation, the application of low-levels of external PEEP can reduce dyspnea, reduce work of breathing, improve patient-ventilator interaction and cardiac function, all without worsening hyperinflation. Neurally adjusted ventilatory assist, a novel strategy of ventilatory assist, may improve patient-ventilator interaction in patients with auto-PEEP.