Radiotherapy-induced fatigue is a common early and chronic side-effect of irradiation, reported in up to 80% and 30% of patients respectively during radiation therapy and at follow-up visits. The factors that cause fatigue and the exact mechanisms responsible for its production, sustenance, or amelioration are not well understood. Multiple correlates and mechanisms have been proposed in the literature and integrated within models of cancer-related fatigue. A multidimensional approach in clinical practice is proposed based on the evaluation of cancer-related fatigue, and on the development of an adequate management. The monitoring system of fatigue used by the authors is presented.