Dysfunction of the mitochondrial (mt) system is thought to play an important role in the mechanism of progression of various neurodegenerative disorders, including demyelinating disorders. They are characterized by neuroinflammation, ultimately leading to neurodegeneration. Mitochondria (mt) dysfunction is closely related to the mechanism of neuroinflammation, causing increased production of reactive oxygen species, which is detrimental to neurons and glia. Vice versa, neuroinflammation is increasingly recognized to produce mt failure, which then contributes to further neuronal injury and degeneration. Multiple sclerosis and X-linked adrenoleukodystrophy are examples of neurodemyelinating diseases that despite having a diverse etiology have in common a progressive course and significant neuroinflammation and neurodegeneration, leading to severe neurologic disability. The scientific community has become increasingly interested in how mt dysfunction relates to neuroinflammation and demyelination and what role it may play in the natural history of progressive demyelinating diseases. Research studies investigating how mt failure contributes to the progression of these conditions are emerging. A better understanding of the role of oxidative stress in progressive inflammatory demyelinating diseases might generate new potential neuroprotective therapeutic approaches for these devastating neurologic conditions.