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Physical and psychological distress is exceedingly common among critically ill patients and manifests generically as agitation. The dangers of over- and undertreatment of agitation have been well described, and the intensive care unit (ICU) physician must strike a balance in the fast-paced, dynamic ICU environment. Identification of common reversible etiologies for distress may obviate the need for pharmacologic therapy, but most patients receive some combination of sedative, analgesic, and neuroleptic medications during the course of their critical illness. As such, understanding key pharmacologic features of commonly used agents is critical. Structured protocols and objective assessment tools can optimize drug delivery and may ultimately improve patient outcomes by reducing ventilator days, ICU length of stay, and by reducing cognitive dysfunction.