Fatigue is one of the most common and debilitating symptoms affecting persons with multiple sclerosis, reported by at least 75% of persons with multiple sclerosis at some point in the disease course. It is also one of the most difficult symptoms to treat, due to its subjective nature and complex pathophysiology. Moreover, other conditions that disproportionately affect persons with multiple sclerosis, including depression and several sleep disorders, may contribute to or be mistaken for the symptom of fatigue, making it difficult to distinguish treatable from untreatable causes. Physicians treating persons with multiple sclerosis should be familiar with the common presentations and definitions of multiple sclerosis-related fatigue, currently proposed causes of fatigue, and approach to treatment. In this clinical article, Dr. Tiffany Braley, Assistant Professor of Neurology and Multiple Sclerosis Specialist at the University of Michigan, provides a review of the common presentations, causes, evaluation, and treatment of multiple sclerosis-related fatigue.