Fatigue, one of the most common symptoms experienced by cancer patients, is multidimensional and is associated with significant impairment in functioning and overall quality of life. Although the precise pathophysiology of cancer-related fatigue is not well understood, a number of metabolic, cytokine, neurophysiologic, and endocrine changes have been described in these patients. A better understanding of these abnormalities is likely to lead to novel therapeutic interventions. Clinically, all patients presenting with significant fatigue should be evaluated for treatable conditions that might contribute to this symptom. Exercise and treatment of anemia are the two most established interventions for cancer-related fatigue. Psychostimulants seem promising based on early studies. Several complementary medicine treatments that showed efficacy in preliminary studies merit further testing.