Cancer-related fatigue (CRF) is either a symptom or a syndrome depending on criteria for diagnosis. CRF is present in 20% to 30% of long-term cancer survivors and 80% to 90% during treatment and at the end of life. Assessment requires determining the presence, severity, and interference with daily activities. Different descriptors for fatigue (eg, tiredness, lack of vigor) measure different patient experiences. Associated factors such as depression, pain, insomnia, dyspnea, anemia, and deconditioning worsen CRF and should be treated if present. Associated factors that contribute to the severity of fatigue differ depending on the stage of cancer. Pharmacologic interventions include recombinant erythropoietin, psychostimulants, corticosteroid, anti-inflammatory drugs other than steroids, and L-carnitine. Advances in the management of CRF will require an understanding of the underlying mechanism before target-specific therapies can be developed.