Acute disseminated encephalomyelitis (ADEM) is an acute autoimmune demyelinating inflammatory disease of the central nervous system. The etiology of ADEM is related to a previous viral infection or vaccination in many cases. The disease is considered multifactorial, with a combination of genetic and environmental factors, such as exposure to infectious agents or immunization. The pathogenesis of ADEM is still not fully understood and is of great relevance for understanding the pathophysiology of the acute demyelinating process and determining the possible outcomes of the disease and its long-term prognosis. We searched for publications on the molecular mechanisms of acute disseminated encephalomyelitis in PubMed, Scopus, ScienceDirect, and Mendeley information databases. This review describes the pathogenesis, clinical phenotypes, and diagnosis of ADEM and summarizes the information currently available on the molecular mechanisms of ADEM, including the results of genomic studies.