The incidence and likely causes of fever of unknown origin (FUO) have changed over the last few decades, largely because enhanced capabilities of laboratory testing and imaging have helped confirm earlier diagnoses. History and examination are still of paramount importance for cryptogenic infections. Adolescents who have persisting nonspecific complaints of fatigue sometimes are referred to Pediatric Infectious Diseases consultants for FUO because the problem began with an acute febrile illness or measured temperatures are misidentified as “fevers”. A thorough history that reveals myriad symptoms when juxtaposed against normal findings on examination and simple laboratory testing can suggest a diagnosis of “fatigue of deconditioning”. “Treatment” is forced return to school, and reconditioning. The management of patients with acute onset of fever without an obvious source or focus of infection is dependent on age. Infants under one month of age are at risk for serious and rapidly progressive bacterial and viral infections, and yet initially can have fever without other observable abnormalities. Urgent investigation and pre-emptive therapies usually are prudent. By two months of age, clinical judgment best guides management. Between one and two months of age, a decision to investigate or not depends on considerations of the height and duration of fever, the patient's observable behavior/interaction, knowledge of concurrent family illnesses, and likelihood of close observation and follow up. Children 6 months–36 months of age with acute onset of fever who appear well and have no observable focus of infection can be evaluated clinically, without laboratory investigation or antibiotic therapy, unless risk factors elevate the likelihood of urinary tract infection.