Pyrexia of unknown origin (PUO) is defined as a fever over 38.3°C lasting more than 3 weeks with no diagnosis after one week of inpatient investigation. Potential causes include infections (bacterial, viral, fungal, parasitic), neoplasms, inflammatory diseases, genetic disorders, and drug reactions. Diagnosis involves detailed history, physical exams, and various lab investigations including blood, urine, and sputum cultures, with treatment often relying on a trial-and-error approach due to the wide range of possible causes.