Magnetic resonance imaging (MRI) techniques have contributed to ameliorate the understanding of the mechanisms responsible for the accumulation of cognitive impairment in patients with multiple sclerosis. Earlier studies demonstrated a relationship of the location of T2-visible lesions in critical brain regions and atrophy of several brain compartments with the severity of cognitive impairment in these patients. More recently, the development of new postprocessing approaches and the application of quantitative MR techniques for the assessment of structural disease-related damage in the brain normal-appearing white matter and gray matter resulted in a better understanding of the factors associated with the onset and development of deficits of several cognitive domains. In addition, the use of functional MRI has disclosed that brain cortical reorganization may play a role in limiting the neuropsychological consequences of structural damage in the different stages of the disease.