Despite being a common clinical sign in practice, investigation of pyrexia can be a considerable challenge. In this lecture, we will cover how to approach the pyrexic patient, review key differences between hyperthermia and pyrexia, consider key differential diagnoses, and discuss how to tackle challenging cases of 'pyrexia of unknown origin'. This lecture will aim to provide a practical approach for managing these cases, using a combination of case examples, important principles, and relevant literature.