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The management of pain, agitation, and delirium in critically ill patients can be complicated by multiple factors. Decisions to administer opioids, sedatives, and antipsychotic medications are frequently driven by a desire to facilitate patients’ comfort and their tolerance of invasive procedures or other interventions within the ICU. Despite accumulating evidence supporting new strategies to optimize pain, sedation, and delirium practices in the ICU, many critical care practitioners continue to embrace false perceptions regarding appropriate management in these critically ill patients. This article explores these perceptions in more detail and offers new evidence-based strategies to help critical care practitioners better manage sedation and delirium, particularly in ICU patients.