We have used ultrastructural techniques to study the pathogenesis of calcifications and psammoma bodies in human thyroid disorders. Particular attention was paid to psammoma bodies associated with papillary thyroid carcinoma which were found to represent the end stages of two different biologic events. The one event took place in the vascular stalk of the neoplastic papillae, starting with a thickening of the base lamina followed by a vascular thrombosis, calcification, and tumor cell necrosis. In the other, intralymphatic tumor thrombi in the thyroid adjacent to the main tumors or in the opposite thyroid lobe became necrotic and calcified. In some instances, destruction of the lymphy vessels led to fibrin exudation and perilymphatic fibrosis. The laminated bodies seen inside thyroid follicles in some nonneoplastic conditions were found to represent inspissated colloid and not considered to be true psammoma bodies. Like the amyloid calcifications seen in medullary carcinoma and the stromal calcospherites seen in several conditions, they seem to lack diagnostic importance. Our findings emphasize the biologic importance of the events leading to psammoma body formation and explain how they may contribute to the indolent course of this type of cancer.