Intraoperative localization of PET-positive recurrent/metastatic lesions can be facilitated using a hand-held PET probe. PET probe is a high-energy gamma probe designed to process the 511 keV photons of PET tracers. Intraoperative gamma probe performance is a function of radiopharmaceutical uptake, clearance kinetics, and probe engineering, all determining the target to background ratio (TBR) and detection threshold. A minimum TBR of 1.5:1 is needed in the operative field for the operating surgeon to be comfortable the differences between tumor tissue and normal adjacent tissue are real. Due to high-energy photon fluxes, achieving a satisfactory TBR intraoperatively is challenging and requires development of a clinically feasible PET-probe guided surgery protocol.