Fatigue is defined as a subjective sensation of tiredness or weariness that occurs at rest. The perception of fatigue among 12-15 years-old Italian adolescents in a school survey was about 70%. Generally the symptoms are reported after a viral illness or an infection. In adolescents with persistent or severe fatigue a selected screening evaluation to look for an underlying organic disorder is warranted. A practical diagnostic approach is given and a brief description of chronic fatigue syndrome is reported according to CDC revised diagnostic criteria published in 1997.