18F-FDG PET is emerging as a useful tool in the staging and restaging of many malignant neoplasms, such as lymphoma, lung cancer, colorectal cancer, head and neck cancer, breast cancer, and melanoma. To accurately interpret 18F-FDG findings one must be familiar with the normal physiologic distribution of the tracer, frequently encountered physiologic variants, and benign pathologic causes of 18F-FDG uptake that can be confused with a malignant neoplasm. The objectives of this article are to (a) describe the mechanism of 18F-FDG uptake, (b) list the patient preparation and pertinent patient history before 18F-FDG imaging, (c) describe the whole-body physiologic distribution of 18F-FDG, (d) list and discuss normal physiologic variants, and (e) list and discuss benign pathologic causes of 18F-FDG uptake.