Fatigue is among the most common, yet least understood, symptoms of multiple sclerosis (MS) [1·]. It can profoundly disrupt the occupational and social functioning of patients, and is recognized as a criterion for MS disability by the Social Security Administration. Most approaches to fatigue assessment can be classified as either self-report scales or performance-based measures of motor or cognitive output. During the clinical management of fatigue, it is important to consider the role of other MS symptoms on fatigue, as well as that of non—MS-related medical conditions. Management of fatigue in MS often entails both pharmacologic and behavioral components. This article reviews recent developments in the assessment, treatment, and pathogenesis of MS fatigue.