Fatigue is one of the most common symptoms people report when visiting health care providers. The causes include contributions from most organs and systems such as the endocrine, musculoskeletal and nervous systems. In addition, the newer concept of central fatigue identifies significant contributions from substances produced by the central nervous system. The cross-talk between the body and brain is crucial to balance potential abnormalities. One of the antidotes to fatigue is exercise and its effects on the biochemical milieu. Better understanding of this process will help prevent and reduce fatigue.