This chapter summarizes immune mechanisms and disease biomarkers of pediatric multiple sclerosis (MS) and acute demyelinating syndromes as well as future directions for research. In adult-onset MS, the hallmark of MS pathology has historically been the perivascular inflammatory lesion, associated with demyelination and axonal injury. Cerebrospinal fluid (CSF) profiles including cellular profiles, oligoclonal bands and IgG Index have been used to characterize MS and differentiate it from other diseases. A study of a large cohort of children with inflammatory demyelination and controls, demonstrated that children with inflammatory central nervous system (CNS) demyelination as well as children with autoimmune diabetes, exhibited heightened peripheral T-cell responses to a wide array of self-antigens. Clinically useful biological markers of inflammation are lacking in both adult- and pediatric-onset MS. N-acetylaspartate (NAA) is selectively synthesized in neurons and considered a marker of the functional integrity of neuronal mitochondrial metabolism.