Cancer-related fatigue (CRF), associated with occurrence of cancer or anti-cancer therapy, is a major symptom of cancer patients. With a high incidence, CRF seriously affects the quality of life and treatment compliance of cancer patients, which has become the focus of cancer research in recent years. CRF may be multifactorial and highly varied in clinical manifestations. At present, several hypotheses have been put forward about the mechanism of CRF. The current article is to review the status quo of the research on the pathophysiological mechanism of CRF.