The term encephalopathy derives from the Greek en-κεφαλι (in the brain) and παθσς (suffering). It is generally defined as a pathobiological brain process characterized by a global disturbance in cognition, which can occur hyperacutely (over the course of seconds to minutes), acutely (over hours to days), subacutely (over weeks to months), or chronically (over years). In that respect, encephalopathy is a syndrome, which recognizes many underlying causes, including both primary neurologic and systemic conditions. The broad number of conditions and the definitional uncertainties make the approach to a patient with encephalopathy challenging. For these reasons, a pragmatic approach is recommended, which includes: careful history taking with particular attention to predisposing factors and time course of onset and evolution of symptoms; pharmacologic history; exposure to toxins; general clinical evaluation and documented extra-neurologic findings; neurologic evaluation including grading of the level of consciousness; presence of delirium and subtypes; metabolic panel and instrumental evaluations.