Symmetric change of the entire area of the bilateral thalami, as with panthalamic lesions, plus involvement of other regions in the brain rarely occurs to previously healthy children. The term, acute necrotizing encephalopathy of childhood, has recently been proposed. Its clinical, radiological, and pathological features are described. This disease predominantly affects infants and young children living in Taiwan and Japan, and manifests itself as acute encephalopathy following 2 to 4 days of fever and minor symptoms of the respiratory and/or gastrointestinal systems. The hallmark of this encephalopathy consists of multifocal, symmetric brain lesions affecting the bilateral thalami, and/or cerebral periventricular white matter, brainstem tegmentum, or cerebellar medulla, which can be documented by ultrasonography, computed tomography, and magnetic resonance imaging of the brain. The prognosis is usually poor. Less than 10% of patients recover completely. Cases with good outcome were reported to have reversible imaging changes. Focal neurologic deficits are common sequelae. The pathogenesis of acute necrotizing encephalopathy of childhood is still not known. Some diseases, such as Reye's syndrome, vascular occlusion, tumor, hemorrhage of the thalamus, Sandhoff disease, or Leigh and Wernicke encephalopathies must be differentiated clinically, radiologically, or pathologically. By excluding other disease entities, acute necrotizing encephalopathy of childhood can be diagnosed.