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Cancer-related fatigue is the most common side effect reported by cancer patients during and after treatment. Cancer-related fatigue significantly interferes with a patient’s ability to perform activities of daily living and maintain functional independence and quality of life. Cancer-related fatigue can also interfere with a patient’s ability to complete treatments. The purpose of this article is to provide an overview of cancer-related fatigue, its pathopsychophysiology, and the role of exercise in the management of this side effect.