Autoradiographs of thyroid glands of aging mice demonstrate the gradual appearance of "cold" follicles which fail to iodinate the intraluminar iodoproteins even after intense exogeneous or endogeneous TSH stimulation. "Cold" follicles first appear at the age of 5 months. They may account for 80% of all thyroid follicles in 13-month-old mice. Morphologically, the "cold" follicles are characterized by a larger than normal colloid volume and a comparatively flat epithelium for any given follicle size. Old thyroids are twice as large as young ones. They contain twice as much normally iodinated thyroglobulin/mg wet weight. The total number of cells per gland remains constant throughout the life time. This is probably also true for the total number of follicles. The iodide pump, as judged by the tissue to serum ratio, remains normal and TSH-responsive. Yet, it is not established whether this is due to a higher activity of the pump in normal follicles or to preservation of inorganic iodide transport in "cold" follicles. Pinocytosis is defective in "cold" follicles and is poorly responsive to TSH stimulation. Furthermore, diffusion of iodocompounds is severely impaired in the colloid of "cold" follicles. It is suggested that the primary defect in the pathogenesis of "cold" follicles in old mice is the gradual failure of endocytosis to respond to normal TSH stimulation. Because exocytosis and iodination would first proceed normally, the follicular lumina would become overdistended up to a point where the apical membrane is functionally impaired. With this sequence of events, "cold" follicles would have impaired iodination while being metabolically as active as hot ones. Thus, several puzzling reports on high metabolic activity of "cold" tissue could possibly be interpreted.