Conventional magnetic resonance imaging (MRI) can improve accuracy in the diagnosis of multiple sclerosis (MS). Metrics derived from conventional MRI are now routinely used to detect therapeutic effects and extend clinical observations. Hyperintense lesions on T2-weighted MRI scans are related primarily to increased water content and thus cannot distinguish between inflammation, edema, demyelination, Wallerian degeneration, and axonal loss. In addition, T2-weighted and post-contrast images are not sufficiently sensitive to detect occult disease affecting normal appearing gray and white matter. They do not show a reliable correlation with clinical measures of disability and do not provide a complete assessment of therapeutic outcomes. In the past few years a host of advanced MRI techniques and analysis methods have been introduced for the assessment of MS. These MRI techniques appear to have better reliability as surrogate markers for monitoring the pathologic processes that most likely are related to disease activity and clinical progression. They are able to reveal a range of tissue changes that include edema, inflammation, demyelination, axonal loss, and neurodegeneration. Therefore, in a disease with a high degree of longitudinal variability of clinical signs and symptoms within and between patients, and with no current adequate biological markers of disease progression, non-conventional MRI techniques provide a powerful tool to non-invasively study pathological substrates of overt lesions and normal appearing brain tissue. In particular, the use of these techniques is promising in elucidating mechanisms underlying the accumulation of tissue damage, repair and functional reorganization of neural pathways in patients with MS.