Altered mental status (AMS) is a syndrome posing substantial burden to patients in the intensive care unit (ICU) in both prevalence and intensity. Unfortunately, ICU patients are often diagnosed merely with syndromic labels, particularly the duo of toxic–metabolic encephalopathy (TME) and delirium. Before applying a nonspecific diagnostic label, every patient with AMS should be evaluated for specific, treatable diseases affecting the central nervous system. This review offers a structured approach to increase the probability of identifying specific causal etiologies of AMS in the critically ill. We provide tips for bedside assessment in the challenging ICU environment and review the role and yield of common neurodiagnostic procedures, including specialized bedside modalities of diagnostic utility in unstable patients. We briefly review two common etiologies of TME (uremic and septic encephalopathies), and then review a selection of high-yield toxicologic, neurologic, and infectious causes of AMS in the ICU, with an emphasis on those that require deliberate consideration as they elude routine screening. The final section lays out an approach to the various etiologies of AMS in the critically ill.