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Altered mental status is a common reason for neurologic consultation. Although it is often due to a systemic infection or metabolic derangement, a host of other etiologies can lead to irreversible brain injury if they are not promptly identified and treated. A systematic approach to the patient is important, with an understanding of when to initiate a more advanced and potentially more resource-intense diagnostic workup.The last decade has seen advances in both the diagnosis and treatment of altered mental status. A significant step forward in the diagnosis of patients with otherwise unexplained encephalitis has been the identification of numerous antibodies associated with paraneoplastic and nonparaneoplastic autoimmune encephalitis. The use of continuous electroencephalography has shown that a significant proportion of otherwise unexplained altered mental status may be caused by nonconvulsive seizures. Several studies have demonstrated that proactive, multicomponent interventions may be effective in preventing hospital-acquired delirium. The recent introduction of dexmedetomidine may lead to decreased rates of delirium in the intensive care unit if the results of clinical trials are borne out in practice.This article discusses causes of altered mental status, an initial approach to evaluating the patient, and elements of the advanced diagnostic workup. The article concludes with a general discussion of prevention and treatment.