About 20% to 30% of patients are difficult to wean from invasive mechanical ventilation. The pathophysiology of difficult weaning is complex. Accordingly, determining the reason for difficult weaning and subsequently developing a treatment strategy require a dedicated clinician with in-depth knowledge of the pathophysiology of weaning failure. This review presents a structural framework ('ABCDE') for the assessment and treatment of difficult-to-wean patients. Earlier recognition of the underlying causes may expedite weaning from mechanical ventilation.