A routine feature of positron emission tomography/computed tomography (PET/CT) imaging is whole-body acquisition that results in many unexpected findings identified outside of the primary region of abnormality. Furthermore, 18F-fluorodeoxyglucose (FDG) is a marker of glycolysis and does not specifically accumulate in malignancy. Understanding the physiology and pathophysiology of normal FDG distribution and common incidental findings is therefore essential to the physician interpreting whole-body FDG-PET/CT studies. Whereas many incidental findings are benign and of limited clinical significance, others represent uncommon manifestations of the primary malignancy, second malignancies, or various clinically significant pathologic processes. Patients with a single malignancy are at greater risk of developing synchronous or metachronous second malignancies, possibly related to exposure to shared carcinogenic agents or presence of prooncogenic mutations. The decision of how to pursue an intervention on the basis of an incidental finding is generally left to clinical judgment.