Most critically ill patients receive a myriad of psychoactive medications during their hospital stay. An understanding of the pharmacology of the more commonly used sedative and analgesic therapies enables the clinician to aptly utilize these medications and limit toxicity. A key to the appropriate provision of sedative and analgesic pharmacotherapy is a thorough patient assessment, use of validated monitoring tools, and defined therapeutic goals. Limiting these therapies while optimizing patient comfort has been shown to reduce the duration of mechanical ventilation and reduce intensive care unit (ICU) and hospital length of stay and should be the aim of the multidisciplinary medical team. This review is intended to provide the reader with a fundamental understanding of how to facilitate comfort of the mechanically ventilated critically ill adult patients and how to minimize medication-related toxicities.