Despite its frequency and high functional impact, very little is known about effective strategies for managing cognitive impairment in multiple sclerosis (MS). Disease-modifying drugs, such as beta-interferons and glatiramer acetate, may prevent or reduce the progression of cognitive dysfunction by containing the development of new cerebral lesions. To date, clinical trials have provided inconsistent results, with neuropsychological effects documented only in one trial. Moreover, pilot studies have tested symptomatic therapies for fatigue, a frequent symptom in MS, which may share a common physiopathological substrate with cognitive dysfunction. Small trials with amantadine, pemoline, 4-aminopyridine and 3-4 aminopyridine have provided mainly negative results. Acetylcholinesterase inhibitors (AChEI) used to treat Alzheimer's disease (AD)-such as donepezil, rivastigmine, and galantamine-have recently been tested in other cognitive disorders, including MS. The majority of pilot trials with AchEI in MS have provided promising results, and the donepezil study recently published by Krupp et al. represents a major development in this field. As for non-pharmacological interventions based on cognitive rehabilitation, few studies have used an experimental approach and, in general, results have been disappointingly negative. Further research is clearly needed in this area.