Fever in the context of a patient with musculoskeletal symptoms is a sign of systemic inflammation. Initial management should be targeted at the identification of the organ systems affected and the search for a precise diagnosis. The main challenge is to differentiate between an infectious aetiology from an immune-inflammatory cause. Patient history and physical examination are key elements in the diagnostic work-up in order to direct appropriate laboratory investigations, as well as radiological and biopsy procedures. Advances in microbiological techniques and molecular genetics have provided additional tools for the clinician. Unfortunately, there is no simple algorithm to direct the diagnostic work-up, which still largely depends on the recognition of patterns of clinical presentations and the corresponding laboratory abnormalities.