Multiple sclerosis (MS) is the most common chronic inflammatory demyelinating disease affecting the central nervous system (CNS) of young adults in Western countries leading, in the majority of cases, to severe and irreversible clinical disability. From the earliest days of magnetic resonance imaging (MRI), it was evident that, because of its sensitivity in revealing focal white matter (WM) abnormalities, it would have become a valuable tool for the assessment of patients with MS. This has been the case in the diagnostic work-up of patients with a suspicious of this condition, as well as in those with confirmed MS, to elucidate the mechanisms underlying disease progression and to monitor the accumulation of pathology underpinning disability. A considerable effort has also been devoted to develop imaging strategies capable of providing an accurate estimate of the extent of disease-related damage. There are established guidelines for integrating MRI findings into the diagnosis of patients who present with clinically isolated syndromes (CIS) suggestive of MS, and specific acquisition protocols have been suggested for monitoring longitudinal changes in patients with an established disease. However, in MS research, conventional MRI has been substantially overcome by quantitative MRI techniques, which have shown greater sensitivity and specificity for assessing the heterogeneous pathological substrates of the disease not only in focal T2-visible lesions, but also in the normal-appearing white matter (NAWM) and gray matter (GM). In addition, the advent of functional imaging techniques, complementing structural/anatomical assessment, is providing novel markers to gather important in vivo pieces of information on brain functions.