Retention of airway secretions is highly common in critically ill patients, on mechanical ventilation (MV). The endotracheal tube (ETT) plays a critical role in this context; indeed, upon inflation of the ETT cuff, mucociliary transport drastically impairs. Additionally, patients with neurological impairments or underlying diseases, i.e. asthma, chronic obstructive pulmonary disease, cystic fibrosis and non-cystic fibrosis bronchiectasis are at the greatest risk. Indeed, in these patients, MV rapidly disrupts the balance between overproduction of mucus and impaired clearance capabilities. Importantly, during MV, mechanically ventilated patients are positioned in the semi recumbent position and several laboratory studies suggested that in this position retained mucus might move toward the distal airways, driven by gravity. Additionally, airflow promotes clearance or retention of retained mucus, via a two-phase gas-liquid flow mechanism. In sedated, invasively ventilated patients, the inspiratory flow can be modulated through the ventilatory settings, and theoretically, mucus clearance could be promoted or hindered through adjustments of the ventilatory settings. Yet, these assumptions should be corroborated in large translational clinical trials. Importantly, humidification of respiratory gases plays an essential role in maintaining mucus clearance rate within the physiologic range. Thus, the most appropriate humidifier should be chosen on a case-by-case basis, and given the reported poor performance of heat-moisture exchanger during ventilation at high minute volumes, heated humidifiers should be a primary choice for patients requiring high ventilatory support. Finally, numerous drugs, commonly used in ventilated patients, i.e. oxygen, inhaled anesthetics, narcotics profoundly affect mucociliary clearance and increase mucus retention. Keywords: Asthma, bronchiectasis, chronic obstructive pulmonary disease, cystic fibrosis, endotracheal tube, mechanical ventilation, mucus clearance.