The study of multiple sclerosis (MS), clinically and pathologically defined in the mid-19th century, recorded numerous advancements during the last decade of the 20th century. Clinically, the disease was more accurately defined by the expected natural history, the clinical subtypes, the scoring of clinical disability, and more defined relationships to environmental factors, such as pregnancy and viral infections. Among the advancements, the notable introduction of 3 agents, interferon beta-1a, interferon beta-1b, and glatiramer acetate, improved the natural history of MS by reducing clinical relapses, delaying progression, and stabilizing the changes seen on cranial magnetic resonance images. Driven by technological expertise, the clinical value of magnetic resonance imaging is extraordinary in that it provides a noninvasive means for demonstrating the dynamic aspects of MS. However, it is essential to resolve early in the next century the discordance between clinical and imaging abnormalities and the uncertain correlative features of magnetic resonance imaging with the natural history of MS. The new millennium is expected to bring rapid progress in clarifying the complex, polygenic influence on susceptibility to MS, to more clearly ascertain the role of injury of axons and myelin, to further clarify the role of surrogate by markers, and to discover new agents to treat the disease limiting demyelination, enhancing remyelination, or improving the function of demyelinated and injured axons.