Dozens of randomized controlled trials have examined whether sedative choice affects outcomes in the ICU. Most compared a benzodiazepine (typically midazolam), the class of sedatives used most frequently in the ICU for several decades, with a non-benzodiazepine sedative, and the large majority of these trials found non-benzodiazepine sedation resulted in better outcomes (Table 27.2). A recent meta-analysis, in fact, found that benzodiazepine sedation (compared with sedation using propofol or dexmedetomidine) delays extubation and discharge from the ICU [11]. These data led the SCCM guidelines [4] to recommend non-benzodiazepines for sedation in the ICU, but questions remain regarding which drug(s) should be preferred. Dexmedetomidine has the benefit of facilitating light sedation and reducing delirium risk [16, 17], but costs remain high and the patient population that benefits the most from this agent has not yet been clearly defined. Propofol is less expensive than dexmedetomidine and less prone to cause oversedation than benzodiazepines but its use in some patients is limited by hemodynamic effects. Other drugs, including opioids, clonidine, haloperidol, and atypical antipsychotics are sometimes used to manage agitation in the ICU, but evidence of benefit in randomized trials is needed before use of these agents can be widely recommended.