Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS), predominantly affecting young females. A review of the role of gender and early age of onset of this disease will be presented. MS can be difficult to differentiate from other demyelinating diseases when it presents before the adult age, particularly from acute disseminated encephalomyelitis (ADEM). Several working definitions and diagnostic criteria have been proposed to differentiate pediatric MS from ADEM. A male predominance seems to occur in the latter, whereas a female predominance is seen in MS patients from puberty; however, a 1:1 ratio has been observed before the age of 12. Neuromyelitis optica (NMO) in children and adolescents shows a clear female predominance. Some cohort studies have suggested that in the last decades, MS tends to initiate at an older age and that the female:male ratio is increasing. Sex hormones may have immunologic implications, but more data are needed to explain the female predominance and its changes over time.