In this article the basic features of the focal MR imaging lesions and the underlying pathology are reviewed. Next, the diffuse pathology in the normal-appearing white and gray matter as revealed by conventional and quantitative MR imaging techniques is discussed, including reference to how the focal and diffuse pathology may be in part linked through axonal-neuronal degeneration. The MR imaging criteria incorporated for the first time into formal clinical diagnostic criteria for multiple sclerosis are next discussed. Finally, a discussion is provided as to how MR imaging is used in monitoring subclinical disease either before or subsequent to initiation of treatment, in identifying aggressive subclinical disease, and treatment of nonresponders.