Fatigue is among the most commonly reported symptoms of patients with cancer, with prevalence exceeding 60% in many studies. It is among the most distressing symptoms associated with cancer and cancer treatments because it substantially disturbs patients' quality of life and ability to function optimally on a daily basis. Although the development of this condition has been associated with a number of factors, its etiology remains poorly understood. Important elements to include in any definition of cancer-related fatigue include its pervasiveness, persistence, detrimental effect on quality of life, and its inability to be relieved by rest or sleep. Several validated questionnaires can be used to measure fatigue in patients with cancer, and research efforts are currently focused on ways to distinguish it from depression with which it shares many symptoms. All patients with cancer should be evaluated for fatigue, and treatment options should be considered for those who are experiencing excessive levels of fatigue. Treatment should be individualized according to the underlying pathology when a specific cause has been identified (e.g., anemia, sleep disorder, depression, or metabolic disorder). Nonspecific therapies may be useful in short- and long-term cancer-related fatigue management in many patients. In addition to older therapies, such as hematopoietics, antidepressants, corticosteroids, and psychostimulants, the effectiveness of the new wake-promoting agent modafinil is currently being studied. A more thorough evaluation of the various therapeutic options is required to better define their efficacy and safety profiles in this patient population.