Acute disseminated encephalomyelitis (ADEM), which is classified as a demyelinating disease of the central nervous system (CNS), is a condition that may be regarded as a bridge linking neurology and the infectious diseases. According to the classic definition, ADEM is a monophasic disease that can arise spontaneously; in most cases, however, it is triggered by systemic viral infections or, more rarely, by vaccinations. As the most recent publications on this topic have shown, ADEM can present a relapsing course, being described as "recurrent" if the affected districts are always the same, or "multiphasic" if there is a dissemination in space and time of the lesions, together with a more or less marked association with polyradiculoneuritis. The clinical features and history of the disease create difficulties in differential diagnosis both with encephalomyelitis caused by infectious agents and with noninfectious inflammatory diseases (other demyelinating syndromes, vasculitis, nonvasculitic autoimmune encephalopathies). This paper describes the main features of ADEM, focusing in particular particular on the factors that influence its outcome and can guide the process of differential diagnosis.