In children and adolescents, multiple sclerosis (MS) has an impact on the developing central nervous system, and can result in transient or fixed deficits of gross motor and/or fine motor skills, sensory perceptual processing, bowel/bladder function, vision, balance, and coordination. In this chapter, the evaluation and care of patients with symptoms of pediatric demyelinating disease are addressed as individual systems with discussion of anatomy and typical features, evaluation measures, and treatment options, including both non-pharmacologic and pharmacologic approaches. Fatigue is the most common symptom experienced by MS patients and is adversely correlated with quality of life. Minimizing fatigue in the pediatric MS population requires a multifaceted approach of eliminating unnecessary energy demands, improving sleep hygiene and optimizing symptomatic medication and disease-modifying treatment (DMT) regimens. The PedsSQ Multidimensional Fatigue Scale has been validated and used in other pediatric chronic diseases such as cancer, inflammatory bowel disease, and rheumatological diseases.