In summary, MS-related fatigue can be a severe problem causing interference with home and vocational activities. There are multiple factors that can contribute to fatigue in MS, and it is important for the patient, family, and clinician to be aware of potential confounders that may worsen fatigue. Clearer understanding about the etiology of fatigue is necessary. Additional larger, randomized, clinical trials are needed to evaluate etiology, pathophysiology, and both pharmacologic and nonpharmacologic interventions. Given the varying nature of fatigue and the limited evidence that fatigue in MS patients is highly dependent on self-perceived scores, additional research into the effect of psychosocial and psychological interventions is recommended. A multidisciplinary approach to fatigue is encouraged when treatments are considered for maximum benefit.