Cognitive dysfunctions are frequent in multiple sclerosis and have a negative impact on employment and quality of life. Pathophysiology of impaired mental activities is probably multifactorial including sensory deafferentation, lesion-related disconnection of associative areas (cortico-cortical and cortico-thalamic), involvement of normal appearing white and gray matter, and direct effects of products of inflammation. Available immunomodulatory treatments for multiple sclerosis may have a role in MS-related cognitive dysfunction because they positively impact some of the pathogenetic studies. Pivotal phase III clinical trials have effectively shown some benefit, confirmed by some post marketing studies. However, results of these studies must be interpreted with great caution because many methodological problems may undermine the quality of the studies.