Cancer patients undergoing treatment often experience a constellation of cancer treatment related symptoms (CTRS) which includes malaise, decreased appetite, sleep disturbance, difficulty thinking, anemia, pain, depressed mood and changes in body composition. These symptoms can greatly influence the subjective sensation of cancer treatment related fatigue (CTRF) which is the most common and distressing CTRS, and one that has a profoundly negative effect on physical functioning and QOL. Cancer patients often display a characteristic pattern of fatigue following treatment; peak fatigue occurring in the days following infusion but returning to baseline before the next chemotherapy cycle. Similar patterns of fatigue occur with each cycle. However, with continuing cycles fatigue levels often do not return to baseline resulting in persistent fatigue which can last for weeks, months and sometimes years after treatment has ended. CTRF can cause delays in treatment, dose reductions or termination of treatment, and has significant social and economic costs. There is also growing evidence that CTRF and its associated decline in physical activity can negatively impact body composition; increasing fat mass while decreasing lean and bone mass. This is of concern because these changes in body composition can impair physical functioning, increase the risk of bone fracture, cardiovascular disease, and cancer recurrence. Given the profound effects that CTRF has on QOL, physical functioning, and long term health, the treatment or prevention of this symptom is an essential component of cancer care. Because of the interrelationship between CTRS and CTRF, we must first understand the molecular mechanisms underlying the initiation and perpetuation of CTRS to effectively treat CTRF. We propose that CTRS/CTRF are initiated and perpetuated by treatment related production of inflammatory cytokines such as IL-1Î² and TNF-Î±. In this regard we propose that these symptoms are the same as sickness behavior a normal physiological response to harmful stimuli caused by increased production of IL-1Î² and TNF-Î± peripherally and in the central nervous system. Our hypothesis is compatible with the emerging area of research on symptom clusters in cancer because we are exploring a potential mechanism for CTRS/ CTRF that may eventually explain the co-occurrence of fatigue, pain, depression, and other commonly experienced CTRSs.