Fever of unknown origin (FUO), with more than 200 potential causes, can represent a real diagnostic challenge. For the work-up of FUO, the first step is to pay attention to each element revealed by a detailed history, a complete physical examination and by some basic diagnostic tests. These elements may constitute some clues that can guide the physician for the prescription of further appropriate diagnostic examinations and procedures. If there is no real specific clues,a pet-scan seems to be useful for the work-up of FUO.