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To review evidence that musclederived interleukin-6 (IL-6) mediates some of the beneficial effects of exercise on cancer treatment-related fatigue (CTRF).Electronic nursing, psychology, and medicine databases.Fatigue is a common and often debilitating symptom associated with cancer treatment. Although the molecular mechanisms underlying CTRF have yet to be fully elucidated, it may be akin to the fatigue associated with “sickness behavior,” which is initiated by the production of the proinflammatory cytokines interleukin-1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α). Physical exercise has been shown to decrease fatigue levels in patients with cancer undergoing treatment. Skeletal muscle selectively produces IL-6 during exercise, and muscle-derived IL-6 can decrease the production and activity of IL-1β and TNF-α. Thus, the anti-inflammatory effects of muscle-derived IL-6 may be a mechanism underlying the observed beneficial effects of exercise on CTRF.Further studies are needed to determine whether the anti-inflammatory effects of exercise underlie its beneficial effects on CTRF.Nurses have proven to be leaders in the field of cancer symptom management. An understanding of potential mechanisms underlying the beneficial effects of exercise on CTRF may help to fine-tune exercise interventions to maximize symptom control and to identify new treatment strategies for fatigued patients with cancer who are unable to participate in an exercise program.