Multiple sclerosis (MS) is the prototypical white matter disease with demyelinating plaques that are typically periventricular and with little mass effect. On contrast-enhanced studies, active “plaques”enhance whereas chronic ones do not. Detection of lesions at the corpus callosum-septum pellucidum interface strongly supports the diagnosis. Chronic disease is characterized by atrophy. MS remains a clinical diagnosis supported by specifie clinical, laboratory, and imaging criteria. Among numerous vascular diseases, senescent white matter changes are typically subcortical and increase in prevalence and number with aging. Posterior reversible encephalopathy syndrome is associated with a variety of agents and diseases and demonstrates a predilection for the posterior cerebral white matter. Viral and post-viral etiologies include acute disseminated encephalomyelitis in immunocompetent patients and progressive multifocal leukoencephalopathy in immunocompromised hosts. Both usually show little mass effect or enhancement on imaging studies. Toxic demyelination results from chronic alcohol abuse, ion balance disorders, and other causes. Cerebral hemispheric and vermian atrophy is common in chronic alcohol abuse while Marchiafava-Bignami and Wernicke encephalopathy are significant complications. Osmotic myelinolysis produces breakdown in the myelinated fibers of the central pons. Iatrogenic causes include radiation therapy and chemotherapy with leukoencephalopathy and/or radiation necrosis.