Fever of unknown origin, bacteremia, and febrile neutropenia are diagnostic challenges. FDG-PET/CT is a well-established modality in infection imaging and the literature increasingly supports its use in these settings. In fever of unknown origin, FDG-PET/CT is helpful, but diagnostic yield depends on patient selection and inflammatory markers. In bacteremia, FDG-PET/CT is cost-effective, reduces morbidity and mortality, and impacts treatment strategy. Although use of FDG-PET/CT in these domains is not established as part of a definitive diagnostic strategy, FDG-PET/CT may help establish final diagnosis in a difficult population and should be considered early in the diagnostic process.