Acute disseminated encephalomyelitis (ADEM) is a monophasic autoimmune demyelinating disease of the central nervous system that typically follows a febrile infection or a vaccination. Children are predominantly affected. A plethora of viral and bacterial pathogens and a number of vaccinations have been associated with ADEM. Experimental animal studies indicate that both primary and secondary autoimmune responses contribute to central nervous system inflammation and subsequent demyelination. The clinical diagnosis of ADEM is strongly suggested by a close temporal relationship between an infectious incident or an immunization and the onset of leukoencephalopathic neurological symptoms. Paraclinical tests may support the diagnosis. Particularly helpful are acute signs of newly developed extensive, multifocal, subcortical white matter abnormalities on magnetic resonance images of the brain. The cerebrospinal fluid may disclose a mild lymphocytic pleocytosis and elevated albumin levels. Oligoclonal bands are not always present in ADEM and, if so, may be transient. The major differential diagnosis of ADEM is multiple sclerosis. Treatment options for ADEM consist of anti-inflammatory and immunosuppressive agents. In general, the disease is self-limiting and the prognostic outcome favorable. In the absence of widely accepted clinical or paraclinical diagnostic guidelines, a number of recently conducted observational case series have substantially broadened our understanding about the clinical phenotype, diagnosis, and prognosis of ADEM.