Fatigue is an extremely common complaint among patients with chronic disease. However, because of the subjective nature of fatigue, and the lack of effective therapeutics with which to treat fatigue, this symptom is often ignored by clinicians, who instead focus on hard, objective disease end-points. Recently, the symptom of fatigue has received greater attention as part of overall health-related quality of life assessments in patients with chronic disease. Furthermore, new methods are being developed to help quantify fatigue, and are being utilized more frequently in the clinical setting. Moreover, studies in patients and using animal models of disease have provided some insight into changes within the brain which appear to be linked to the genesis of central fatigue. This review focuses on fatigue in chronic disease and outlines possible mechanisms which may give rise to central fatigue in chronic disease. Moreover, methods for measuring fatigue and an approach to the fatigued patient are discussed. Hopefully, a broader understanding of this distressing symptom will lead to the development of specific therapies for treating fatigue in these patients.