Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS), often beginning in late adolescence and early adult life. The etiology of MS has not yet been fully elucidated, and it is attributed to both genetic and environmental causes. Accumulating data indicate that oxidative stress (OS) plays a major role in the pathogenesis of MS. Reactive oxygen species (ROS), leading to OS, generated in excess primarily by macrophages, have been implicated as mediators of demyelination and axonal damage in both MS and its animal model: experimental autoimmune encephalomyelitis (EAE). ROS cause damage to cardinal cellular components such as lipids, proteins, and nucleic acids, thereby resulting in cell death. Weakened cellular antioxidant defense systems in the CNS of MS patients resulting in increased vulnerability to ROS effects may increase CNS damage. This chapter reviews the current knowledge on OS in MS and possible antioxidant treatments.