Cancer-related fatigue (CRF) is a multifactorial, biobehavioral phenomenon experienced by the majority of persons with cancer. It has negative consequences on the individual's physical functioning and quality of life. An array of biological, psychobehavioral, and functional mechanisms contributes to its occurrence. A relatively large number of studies have examined the effect of physical exercise on CRF over the past few decades. Most of these studies did not specifically examine the effect of physical exercise on the biobehavioral mechanisms underlying CRF. For the most part, these studies have not been guided by a consistent theoretical model. Consequently, the mechanisms by which exercise may ameliorate CRF are not fully elucidated. A theoretical model incorporating fatigue-related biobehavioral variables that could be affected by physical exercise will allow for effective knowledge development in this area and could lead to the development and refinement of exercise protocols that specifically target these mechanisms. Thus, the purpose of this paper is to present a comprehensive theoretical model to guide future research on the effectiveness of exercise interventions in CRF. The proposed model incorporates the biological, psychobehavioral, and functional variables implicated in the induction of CRF.