Numerous research studies indicate that a subgroup of patients with multiple sclerosis (MS) experience cognitive and emotional deficits that correspond to degenerative brain changes. In some instances, neuropsychological impairment may be the initial and/or predominant symptom of MS. These observations underscore the need for neuropsychological evaluation as a critical component in the diagnostic evaluation and treatment of MS patients. In the current paper clinical issues relevant to the neuropsychological assessment of MS patients are reviewed and a proposal for comprehensive testing is presented.