Acute febrile illnesses are common reasons to seek healthcare globally. They can be caused by diverse infectious diseases which require complex diagnostics. Current clinical guidelines provide guidance on how to manage severe illness, common localizing infections like pneumonia and urinary tract infections, as well as malaria. How to manage other cases of acute febrile illness is less clear and is the focus of this review. Without an etiologic diagnosis, clinicians frequently prescribe empiric antibiotics that may be unnecessary or inadequate. We reviewed recent studies on the etiology of acute febrile illnesses in adults and adolescents that employed multiple diagnostic modalities, including rapid diagnostic tests, serologies, and polymerase chain reaction. Although studies and etiologies were heterogenous, we enumerated the causes of febrile illness in these studies. Possible improvements in clinical decision-making algorithms are discussed.