Technetium-99m sestamibi planar and single-photon-emission computed tomographic scintigraphy is useful in the diagnosis of parathyroid gland disease. To understand the various patterns of parathyroid disease, it is important to understand parathyroid embryology and anatomy. The spectrum of parathyroid disease demonstrated with Tc-99m sestamibi scintigraphy includes eutopic disease, ectopic disease, solitary adenoma, double or multiple adenomas, cystic adenoma, lipoadenoma, multiple endocrine neoplasia, hyperfunctioning parathyroid transplant, entities with atypical washout, and nonparathyroid entities that take up Tc-99m sestamibi. The diagnosis of parathyroid tumors with Tc-99m sestamibi scintigraphy is based on the difference in clearance rates between the thyroid and diseased parathyroid glands, and any condition that interferes with radiotracer clearance will limit the effectiveness of the study. The technique is most clearly indicated for the preoperative evaluation of recurrent or persistent hyperparathyroidism, but it is increasingly being used before the initial surgical exploration as well. Subtraction Tc-99m sestamibi and iodine-123 scintigraphy may be helpful in difficult cases. Parathyroid hyperplasia, multisite parathyroid disease, and concomitant thyroid and parathyroid disease remain potential hurdles for this scintigraphic technique, and optimal handling of these problems still relies heavily on the skill and experience of the endocrine surgeon.