Intensive care patients are older, frailer, and more co-morbid than ever before, and remain at risk of a variety of adverse outcomes, both in ICU, and after discharge. Sedation and delirium play an intricate role in this complex system, and it can be difficult to determine if they are a contributor or consequence in any given situation. During the COVID-19 pandemic, the increased frequency of complex ventilatory management, including prone ventilation and neuromuscular blockade, necessitated deep sedation in many cases. In concert with infection control concerns and staffing pressures, the delivery of precision symptom- and patient-oriented sedation has waned in favour of strategies felt to be globally safe. Using the SPICE III study as a lens to understand both the importance of exploring heterogeneity of effect in large, complex RCTs of critically ill patients, and the importance of an individualised approach to sedation in the intensive care unit, we demonstrate the evolution of our understanding of sedation in this challenging environment. By following the principles that define the cornerstones of best contemporary sedation practice we can once more grow beyond the boundaries of clinical practice guidelines in the provision of personalised, patient-orientated sedation in the post-COVID intensive care unit.