Cancer patients frequently suffer from fatigue and loss of physical performance. Several biologic, psychologic, and social factors have been suggested as explanations for the origins of fatigue in this context. In most cases, fatigue has a multifactorial genesis. However, recent studies suggest that fatigue may originate from alterations in the muscular energetic systems caused by cancer and its treatment. Furthermore, there is growing evidence that physical exercise programs help prevent the manifestation and reduce the intensity of cancer-related fatigue. In this article, actual evidence of the relationship between fatigue and impairment of physical performance in cancer patients and suggestions for new directions for research are discussed. Cancer 2001;92:1689–93. © 2001 American Cancer Society.