Fever of unknown origin (FUO) can be caused by a wide group of diseases, and can include both benign and serious conditions. Since the first definition of FUO in the early 1960's, several updates to the definition, diagnostic and therapeutic approaches have been proposed. This review outlines a case report of an elderly Italian male patient with high fever and migrating arthralgia who underwent many procedures and treatments before a final diagnosis of Adult-onset Still's disease was achieved. This case report highlights the difficulties in diagnosing certain causes of FUO that requires a very high index of suspicion. The main causes of FUO in paediatric and adult patients will be reviewed here, underlying the fact that a physician should also consider the possibility that a patient with FUO may have a monogenic autoinflammatory disease (AID). The identification of AIDs requires a careful evaluation of both history and clinical details that may reveal important clues to identify the correct aetiology. We also provide a comprehensive account of specific signs and symptoms that could suggest possible diagnoses and guide the work-up of FUO and non-genetic periodic fevers in children.