Radiotherapy-induced fatigue is a common early and chronic side-effect of irradiation, reported in up to 80 and 30% of patients during radiation therapy and at follow-up visits, respectively. It is frequently underestimated by medical and nursing staff, only about 50% of patients discuss it with a physician and in one fourth of cases any intervention is proposed to the patient. The patients rarely expect fatigue to be a side-effect of treatment. The etiology of this common symptom, its correlates and prevalence are poorly understood. In numerous studies the level and time course of fatigue was demonstrated to depend on the site of tumor and treatment modalities. For example, psychological mechanisms have been proposed to explain fatigue in women receiving irradiation for early breast cancer, whereas decline in neuromuscular efficiency rather than psychological reasons can lead to the fatigue observed in patients undergoing radiotherapy for prostate cancer. Fatigue can affect global quality of life more than pain, sexual dysfunction and other cancer- or treatment-related symptoms. Several interventions have been tested in the management of radiotherapy-related fatigue and some randomized studies have been recently published. Although an optimal method has not yet been established, some promising results have been reported with relaxation therapy, group psychotherapy, physical exercise and sleep. Further methodologically correct studies are warranted to define better the causes, optimal prevention and management of this symptom.