Pediatric multiple sclerosis (MS) represents only 2-5% of the MS population, but children with MS have a higher relapse rate and reach permanent disability at a younger age than adult-onset MS. Early and accurate diagnosis of pediatric MS is vital for prompt treatment to mitigate ongoing neuroinflammation and irreversible neurodegeneration. However, it is difficult to differentiate MS from acute disseminated encephalomyelitis (ADEM) and neuromyelitis optica (NMO) in pediatric patients, even considering the clinical, magnetic resonance imaging (MRI), and paraclinical findings, because the first presentation of inflammatory demyelination in children is often atypical. The purpose of this review is to summarize the clinical, neuroimaging, and paraclinical key differences between pediatric patients with MS, ADEM, and NMO and to discuss novel biomarkers, such as antibodies to aquaporin-4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG), which may help in making a diagnosis.