Cancer-related fatigue is a common and distressing side effect of cancer and its treatment, often persisting for years after treatment. It significantly impacts quality of life and may be a risk factor for reduced survival. The mechanisms underlying cancer-related fatigue are complex and involve inflammation, with studies showing links between inflammatory markers and fatigue before, during, and after treatment. Variability in fatigue experiences is not fully explained by disease or treatment characteristics, suggesting host factors play a role. Longitudinal studies have identified genetic, biological, psychosocial, and behavioral risk factors for fatigue. Various interventions, including physical activity, psychosocial, mind-body, and pharmacological treatments, have been examined in randomized controlled trials. While no gold standard exists, several approaches show beneficial effects. Inflammation is a key pathway, with pro-inflammatory cytokines playing a significant role. Fatigue is associated with elevated inflammatory markers such as CRP, IL-6, and TNF-α. Inflammation and fatigue are also linked to changes in the HPA axis, autonomic nervous system, and immune function. Genetic factors, such as SNPs in inflammation-related genes, may increase risk for fatigue. Psychological and biobehavioral factors, including pre-treatment fatigue, depression, sleep disturbance, and physical inactivity, are also risk factors. Treatments include exercise, psychosocial interventions, mind-body approaches, and pharmacological agents. Exercise, particularly aerobic exercise, is effective in reducing fatigue. Psychosocial interventions, such as cognitive-behavioral therapy, have shown benefits. Mind-body interventions like acupuncture, mindfulness, yoga, and biofield therapy may also be helpful. Pharmacological treatments, including hematopoietic growth factors, methylphenidate, and modafinil, have shown some efficacy. Overall, a multi-faceted approach is needed to address cancer-related fatigue, with ongoing research aimed at identifying effective interventions and understanding underlying mechanisms.Cancer-related fatigue is a common and distressing side effect of cancer and its treatment, often persisting for years after treatment. It significantly impacts quality of life and may be a risk factor for reduced survival. The mechanisms underlying cancer-related fatigue are complex and involve inflammation, with studies showing links between inflammatory markers and fatigue before, during, and after treatment. Variability in fatigue experiences is not fully explained by disease or treatment characteristics, suggesting host factors play a role. Longitudinal studies have identified genetic, biological, psychosocial, and behavioral risk factors for fatigue. Various interventions, including physical activity, psychosocial, mind-body, and pharmacological treatments, have been examined in randomized controlled trials. While no gold standard exists, several approaches show beneficial effects. Inflammation is a key pathway, with pro-inflammatory cytokines playing a significant role. Fatigue is associated with elevated inflammatory markers such as CRP, IL-6, and TNF-α. Inflammation and fatigue are also linked to changes in the HPA axis, autonomic nervous system, and immune function. Genetic factors, such as SNPs in inflammation-related genes, may increase risk for fatigue. Psychological and biobehavioral factors, including pre-treatment fatigue, depression, sleep disturbance, and physical inactivity, are also risk factors. Treatments include exercise, psychosocial interventions, mind-body approaches, and pharmacological agents. Exercise, particularly aerobic exercise, is effective in reducing fatigue. Psychosocial interventions, such as cognitive-behavioral therapy, have shown benefits. Mind-body interventions like acupuncture, mindfulness, yoga, and biofield therapy may also be helpful. Pharmacological treatments, including hematopoietic growth factors, methylphenidate, and modafinil, have shown some efficacy. Overall, a multi-faceted approach is needed to address cancer-related fatigue, with ongoing research aimed at identifying effective interventions and understanding underlying mechanisms.