BACKGROUND: Although fatigue is one of the most common complaints of patients with cancer, it went unrecognized or overlooked for many years, until clinicians achieved better control over the more acute symptoms of nausea, emesis, and pain. A number of treatment-related and disease-related factors may contribute to the development of fatigue, but its physiologic basis remains poorly understood, and many proposed interventions have not been studied systematically. The lack of a standard of care for the assessment or treatment of fatigue in patients with cancer has limited research in this field. A critical appraisal of these issues is presented in this review. METHODS: The published literature was reviewed for definition, prevalence, causes, and means of managing cancer-related fatigue (CRF). RESULTS: Fatigue was reportedly present at the time of diagnosis in approximately 50-75% of cancer patients. The prevalence of CRF increased to 80-96% in patients undergoing chemotherapy and to 60-93% in patients receiving radiotherapy. Two tested interventions that showed consistent effects to alleviate CRF were treatment of cancer-related anemia with erythropoietin agents (recombinant human erythropoietin and darbepotin alpha) and aerobic exercise. CONCLUSIONS: Several lines of research are needed to bridge the specific gaps in the current knowledge of CRF. These involve the pathophysiology of the symptom, the validation of diagnostic criteria, and specific therapeutic interventions. Current practice guidelines are based on a combination of research and expert clinical judgment and should be used to guide care with the expectation that they will evolve to incorporate the results of studies currently underway.