Leukoencephalopathy is a syndrome of neurologic deficits, including alteration of mental status, caused by pathologic changes in the cerebral white matter. The term, toxic leukoencephalopathy, encompasses a wide variety of exposures and clinical presentations. The diagnosis in these syndromes is made by careful attention to the history, clinical features, and radiologic findings. This article details three of the best-defined toxic leukoencephalopathies: delayed posthypoxic leukoencephalopathy, including delayed neurologic sequelae after carbon monoxide poisoning; heroin inhalation leukoencephalopathy; and posterior reversible encephalopathy syndrome.