This chapter describes the proposed clinical and pathologic definitions of acute disseminated encephalomyelitis (ADEM) and discusses the clinical utility and limitations of individual criteria for ADEM. A practical approach for evaluation and treatment of ADEM for clinicians are outlined. ADEM is traditionally considered an uncommon monophasic, acute or subacute, multifocal, idiopathic inflammatory demyelinating disease (IIDD) that predominantly involves the white matter of the central nervous system (CNS). The pathologic hallmark of ADEM is perivenular inflammation with limited sleeves of demyelination. Retrospective studies using various clinical criteria for ADEM led to several clinical, laboratory, and imaging observations that are associated with a final diagnosis of ADEM versus multiple sclerosis (MS). The utility and limitations of these observations for application in clinical practice are discussed. Multiple clinical factors should be considered in combination before arriving at a probable diagnosis of ADEM, including (1) presenting signs and symptoms; (2) conventional and advanced MRI abnormalities; (3) sufficient follow-up confirming a monophasic course based on clinical and/or neuroimaging criteria; (4) lack of alternative diagnosis; and (5) brain histopathology if available. It is unclear whether ADEM presents differently in adults than in children, specific criteria should be applied with caution in adults.