Although research supports the minimization of sedation in mechanically ventilated patients, many patients with severe acute respiratory distress syndrome (ARDS) receive prolonged opioid and sedative infusions. ICU teams face the challenge of weaning these medications, balancing the risks of sedation with the potential to precipitate withdrawal symptoms. In this article, we use a clinical case to discuss our approach to weaning analgosedation in patients recovering from long-term mechanical ventilation. We believe that a protocolized, multimodal weaning strategy implemented by a multidisciplinary care team is required to reduce potential harm from both under- and over-sedation. At present, there is no strong randomized clinical trial evidence to support a particular weaning strategy in adult ICU patients, but appraisal of the existing literature in adults and children can guide decision-making to enhance the recovery of these patients.