Acute and chronic radiotherapy-related fatigue occurs in up to 80% and 30%, respectively, of patients undergoing irradiation for cancer. Frequently, the symptom is not expected by the patients and is underestimated by medical and nursing staff. Fatigue can affect global quality of life more than pain, sexual dysfunction and other cancer- or treatment-related symptoms. Its etiology and correlates are not clear. Published reports are mainly descriptive, and in many of them numerous methodological biases are present. One of the limitations is lack of a standard method of assessment that could simplify the comparison between different series. In the last decade, modern instruments have been designed to measure fatigue. They include uni- and multidimensional tools. Use of these specific instruments is highly recommended for research on radiation-related fatigue. In daily practice when time is limited, simple assessment is necessary. For example, systemic use of plain and easily understandable questions about fatigue, its level and impact on daily life could be sufficient and reliable. Therapeutic strategies for radiotherapy-induced fatigue have not yet been clearly defined, but a few randomized studies have been recently published. Physical exercise, group psychotherapy and relaxation therapy have been demonstrated to be effective. Moreover, pharmacological treatment of concomitant disturbances (anemia, pain, insomnia, depression, dehydration, infection, malnutrition) and other radiotherapy side effects (diarrhea, hormonal insufficiency etc.) should be considered. Further methodologically correct studies are warranted to better define the causes, optimal prevention, assessment and management of this symptom.