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Abstract One of the most frequent symptoms in multiple sclerosis (MS) is fatigue. It has a major impact on quality of life as well as on professional activity. Even nowadays it is still unclear what constitutes an adequate assessment of the perceived fatigue. The following overview will discuss different possibilities to assess fatigue with the help of questionnaires, clinical interviews or the objective measurement of cognitive performance. Furthermore, a structured guideline for the assessment of fatigue will be proposed. Clinical criteria for MS related fatigue include the main symptoms, their everyday relevance, the possible causal relation with the cause of disease (the underlying MS), as well as an exclusion of other possible somatic or psychological reasons. It is recommended to use the “Würzburger Erschöpfungs-Inventar bei Multipler Sklerose (WEIMUS)” (English: Würzburg Fatigue Inventory for Multiple Sclerosis) and especially the “Fatigue Scale for Motor and Cognitive Functions” (FSMC), as these questionnaires distinguish between motor and cognitive fatigue and due to the larger number of research studies using the FSMC. Moreover, the presence of depression, quality of sleep and daytime sleepiness should be assessed. In addition, general cognitive performance as well as performance during monotonous stimulation (vigilance) should be assessed. This may be relevant for the evaluation of a patient’s capacity to work, and for determining prognosis, as there are indications for a relation to relapse frequency, a change from a clinically isolated syndrome (CIS) to an MS diagnosis with an increase of brain atrophy. All in all, it can be said, that despite the growing convergence of diagnostic criteria, the available studies of the objective as well as the subjective assessment of fatigue are still not sufficient and further research is needed.