Fatigue is one of the most common and distressing symptoms experienced by cancer patients. Research conducted over the past few years has documented that initiation of radiation therapy typically results in significant increases in fatigue severity. Preliminary evidence suggests that, among disease-free patients, this heightened fatigue remits to levels approaching those reported before initiation of treatment in the weeks or months after treatment completion. Potential sources of fatigue are varied and may include anemia, cytokine activation, psychological distress, concomitant symptoms and side effects, and concurrent medications. Efforts to manage fatigue in cancer patients should focus on correcting potential etiologies and relieving symptoms. For patients experiencing fatigue related to anemia, treatment with an erythropoietic agent should be considered. Preliminary evidence suggests that moderate exercise during radiation therapy may also be helpful in relieving fatigue. Additional research is needed to evaluate the effectiveness of these therapies as well as other intervention strategies, such as the use of antidepressant and psychostimulant medications.