Several factors that influence physiologic 18F-fluorodeoxyglucose (FDG) uptake and general FDG distribution may affect PET/CT imaging in infection and inflammation. The general impact of hyperglycemia on the diagnostic performance of FDG-PET/CT is probably less in infection/inflammation than in malignancy. Patient preparation may reduce physiologic FDG uptake, but recommendations are less established than in malignancy. Local implementation of various patient preparatory measures should reflect the specific patient population and indications. This article outlines some of the challenges with physiologic FDG distribution, focusing on infectious and inflammatory diseases, and potential countermeasures and patient preparation to limit physiologic uptake before scan.