FDG-PET has been proven to be very sensitive in detecting a large variety of carcinomas. The FDG accumulation in malignant tumors is quite stereotyped and often reflects the aggressiveness of the tumor. Therefore, FDG appears to be suitable to detect unknown primaries independent of the type of disease. Being unaware of the site of the primary and also being unaware of the intensity of glucose metabolism, the interpretation of FDG-PET images needs rules accepting a reduced specificity for the definition of malignancy. However, due to physiological FDG-uptake in the head and neck area, especially in lymphatic tissue and vocal cords, one has to accept a high rate of equivocal findings interpreting FDG-PET alone. In this situation, the use of dual-modality PET/CT is of particular value. It allows for correlating the suspicious or unclear PET finding directly with morphology and by that the rate of false-equivocal or false-positive findings is reduced. In addition, PET/CT can precisely define the site of the PET finding in terms of anatomy, helping to direct the surgeon. This characteristic is of different value depending on the location of the primary and tends to be of utmost importance in the head and neck area. Finally, CT by itself may contribute with the detection of PET-negative findings. Thus in conclusion, PET and PET/CT can help localize the primary in CUP in approximately 40% of all cases, even after a thorough work-up with a variety of other investigations.