Abstract Enterovirus D68 (EV-D68), a neurotropic respiratory pathogen, poses a considerable clinical threat through its link to pediatric acute flaccid myelitis (AFM) and severe respiratory illness . The possibility of recurrent epidemics , evidenced since the 2014 outbreak, remains a major concern . Genomic determinants of virulence are central to this threat. Sequence variations that affect host–receptor interactions , immune evasion, and replication efficiency serve as critical modifiers of pathogenicity. This article systematically reviews the evidence for specific genomic sites that enhance EV-D68 virulence , focusing on three critical regions: the VP1 receptor-binding site , the 2Apro/TRAF3 cleavage site, and the 3Cpro immunoregulatory region . Mutations in the VP1 receptor-binding site can alter affinity for host receptors such as sialic acid, heparan sulfate, and MFSD6 , thereby shaping viral entry and tissue tropism . Alterations in the 2Apro/TRAF3 cleavage site may impair pro...