The strong and potentially reciprocal relationship between cancer-related fatigue (CRF) and disrupted sleep-wake patterns suggests a possible shared physiologic pathway. A growing body of evidence supports this and shows that abnormalities in the 24-hour rhythm of stress-related hormones may be related to chronic fatigue and sleep disturbances. Aberrations in the hypothalamic-pituitary-adrenal (HPA) axis, the primary neuroendocrine interface responding to stress, induce important biologic and behavioral consequences. HPA aberrations have long been associated with chronic fatigue syndrome. Many overlapping symptoms exist between chronic fatigue syndrome and CRF, including sleep disruption. Therefore, in the absence of knowledge about CRF mechanisms, emerging biologic models from chronic fatigue syndrome may assist in understanding the cause of CRF. Cancer-associated stressors also may alter the circadian functions of HPA-associated neuroendocrine activities, which result in the symptoms of fatigue and disrupted sleep-wake patterns in patients with cancer. Exploring promising physiologic models furthers the knowledge about CRF and disrupted sleep and may foster hypothesis-based studies of mechanisms that underlie apparent overlapping symptoms, providing the basis for new management to improve sleep and lessen fatigue.