Management of pain, agitation, and delirium is a complex process requiring a multimodal approach to optimize patient outcomes. Dexmedetomidine is a centrally acting alpha-2 agonist with sedative and analgesic properties that has demonstrated efficacy in managing pain, agitation, and delirium in a variety of critically ill patient populations. Dexmedetomidine has demonstrated the ability to provide a mild to moderate level of sedation in diverse ICU populations compared to conventional sedative regimens. Recent literature has demonstrated improved outcomes with dexmedetomidine based vs. benzodiazepine based sedation therapy in select mechanically ventilated ICU patients. However, dexmedetomidine therapy has also been associated with adverse cardiovascular events including hypotension, bradycardia, and asystole. The clinical pharmacology, therapeutic efficacy, safety considerations, controversies, and future directions of dexmedetomidine therapy in the ICU setting will be discussed.