Fatigue is often related to cancer, and that related to its treatment is the most commonly reported side effect of cancer treatment. It differs from that induced by other causes, such as sleep disturbance and exertion, as the latter are typically alleviated by a period of rest. In contrast to exercise-induced fatigue, the fatigue reported by cancer patients is usually described as an unusual, excessive, whole-body experience that is disproportionate or unrelated to activity or exertion and is not relieved by rest or sleep. Cancer-related fatigue is a subjective experience that has a clear detrimental effect on a cancer patient's quality of life and ability to sustain the usual personal, professional, and social relationships. The fatigue can be pervasive: cancer patients frequently report that fatigue begins with treatment, continues during the course of chemotherapy or radiation treatment, and declines somewhat – but frequently sustains at a higher-than-baseline rate – after treatment is over. It may also persist for several years even in patients with no apparent disease. While a number of researchers have speculated about the nature of cancer-related fatigue, there has been little systematic research on its etiology or treatment. In many aspects our knowledge of the fatigue mechanisms in cancer patients is at a similar stage to that reached in our understanding of anti-cancer therapy-induced nausea and vomiting about 20 years ago. This paper introduces four plausible hypotheses for the development of fatigue. Evidence available to support a role for anemia, adenosine triphosphate, vagal afferents, and the interaction of the HPA/cytokines and 5HT is discussed.