Fatigue is common in people with multiple sclerosis (MS) and symptoms of fatigue are often reported as the most debilitating symptoms of the disease. However, there are few reports of interventions for fatigue in MS. A systematic review of published literature examining pharmacological and psychosocial/psychological interventions for fatigue in MS was conducted. The search and review strategy undertaken used the Centre for Reviews and Dissemination guidelines. Papers were reviewed by two independent reviewers. Of 81 studies short-listed for inclusion, 15 studies were included, of which 10 were studies of pharmacological therapy and five were studies of psychosocial/psychological interventions. Of the pharmacological studies, two were rated as of moderate-to-high quality, three of moderate quality, two of moderate-to-low quality and three of low quality. Of the psychosocial/psychological studies, three were rated as of moderate quality and two of moderate-to-low quality. None of the studies reviewed reached the highest level of quality according to pre-agreed criteria. Regardless of level of quality, effectiveness of both pharmacological and psychosocial/psychological interventions was modest at best and often absent. Accordingly, there is little evidence-based advice that can be offered to people with MS to help manage their fatigue.