Clinically significant pain has been found in as many as 65% of persons diagnosed with multiple sclerosis (MS). Acute pain conditions include trigeminal neuralgia, painful optic neuritis, and Lhermitte's syndrome. Chronic pain conditions such as dysesthesias in the limbs, joint pain, and other musculoskeletal or mechanical pain problems develop as a function of spasticity and deconditioning associated with MS. These painful conditions may respond to pharmacological, surgical, rehabilitation, and psychological interventions. However, unresolved pain, associated disability, and affective distress are common. In addition, efforts to manage MS and its associated symptoms, for example, may inadvertently cause osteoporosis and headache or other symptoms that may exacerbate pain and pain-related disability. Conversely, efforts to manage pain may have negative effects on the symptoms of MS (e.g., increased fatigue). A multidimensional approach to assessment and management that is guided by a comprehensive biopsychosocial model is recommended. Such an approach needs to consider the exacerbating nature of MS, MS-related pain, and interventions aimed at their management. Suggestions for future research on MS-related pain conclude the article.