Secretion management in mechanically ventilated patients is a paramount task for clinicians. A better understanding of the mechanisms of flow bias and airway dynamic compression during airway clearance therapy may enable a more effective approach for this population. Ventilator hyperinflation, expiratory rib cage compression, a PEEP-ZEEP maneuver, and mechanical insufflation-exsufflation are examples of techniques that can be optimized according to such mechanisms. In addition, novel technologies, such as electric impedance tomography, may help improve airway clearance therapy by monitoring the consequences of regional secretion displacement on lung aeration and regional lung mechanics.