Cancer-related fatigue (CRF) is a disabling and distressing symptom that is highly prevalent across the cancer continuum from a patient's diagnosis and treatment through survivorship and end of life. It has a multifactorial etiology and significant individual variability in its clinical expression, determinants, and sequelae. Despite the significance of CRF, it is often underdiagnosed, and management is frequently suboptimal. This review synthesizes the state of the science concerning the features, possible mechanisms, and predictors of CRF; offers recommendations for the evaluation of CRF; and appraises the strength of the evidence for a wide range of pharmacologic and nonpharmacologic interventions to prevent and manage fatigue during and after cancer and its treatment. There is evidence from methodologically rigorous controlled trials that exercise, psycho-educational interventions, and cognitive-behavioral therapy for insomnia are effective in the treatment of CRF, and a wide range of pharmacologic and nonpharmacologic interventions has shown initial promise in single-arm pilot studies with small, heterogeneous samples. Rigorously designed and adequately powered randomized trials are warranted to (1) determine the effectiveness of promising approaches and (2) identify the interventions that are most effective in treating CRF in specific subpopulations (eg, stem cell transplant recipients, older adults, patients with lung or colorectal cancers, survivors, and those at the end of life). Studies to elucidate the biologic expression profiles of CRF, to explicate the mechanisms through which particular interventions impact CRF, and to identify the mediators and moderators of fatigue outcomes will ultimately permit individually tailored approaches for the treatment of CRF.