The definitive treatment of primary hyperparathyroidism (PHPT) is the surgical approach which traditionally consists of bilateral neck exploration with visualization of at least 4 parathyroid glands and removal of the enlarged ones. However, the most frequent cause of PHPT is a solitary parathyroid adenoma so that a limited neck exploration in order to remove the solitary adenoma alone appears adequate to many surgeons. The recent significant improvements achieved in the pre-operative parathyroid localization techniques, mainly the parathyroid scintigraphy, and the introduction in surgical practice of measurement of quick parathyroid hormone, endoscopic procedures, and intra-operative gamma probes used together specific radiopharmaceuticals allowed to offer the PHPT patient a limited neck exploration as the unilateral neck exploration and the minimally invasive parathyroidectomy. The present article deals with the role of the intra-operative gamma probes used together with specific radio-pharmaceuticals, discussing the principal advantages and disadvantages of each currently used radio-guided approach.