Pyrexia of unknown origin (PUO) is a frequent presentation to the Acute Medical Unit, and is a source of significant morbidity, both the psychological burden of an uncertain diagnosis and prognosis and untreated complications of the underlying pathology. We present a problem based review of the management of PUO, illustrated by a patient who recently presented to our unit with fever and systemic malaise after returning from abroad and in whom no cause could be found for more than two months. We describe a structured approach making use of complex modern techniques such as Positron Emission Tomography-Computed Tomography (PET-CT) which ultimately provided the diagnosis for our patient.