Despite sufficient iodine supply, goiter continues to be of considerable surgical significance in formerly endemic countries. It now appears that iodine deficiency and increased thyrotropin stimulation are not the only causes of goiter. Xenotransplantation of human thyroid tissue onto nude mice allowed study of the regulation of growth and function in human goiter tissue. Grafts of human thyroid tissue growing in nude mice could be shown to react to endogenous mouse thyrotropic stimulation and suppression. 131I autoradiographs of xenotransplanted goiter tissue showed as marked a heterogeneity as did the original goitrous tissue prior to transplantation. There was no firm correlation between the morphologic appearance of a follicle and its iodine metabolism. Scintigraphically "cold" and "hot" goiter tissue differed from each other quantitatively but not qualitatively; i.e., both "hot" and "cold" tissue were composed of metabolically active and nonactive follicles. Iodine organification was not completely suppressible by thyroxine treatment; this indicates autonomous functional activity. The distribution of proliferating tissue labeled by 3-H-thymidine did not parallel the distribution of functionally active tissue labelled by 131I. Thyroxine treatment did not completely inhibit 3-H-thymidine incorporation, indicating autonomous growth. Thus, our pathogenetic concept of goiter formation is based on three mainstays: (1) goiter heterogeneity, (2) autonomy of growth and function, and (3) dissociation of growth and function in human goiter tissue. Thus, the surgeon dealing with goiter ought to remove all pathologically altered tissue, i.e., nodular tissue, irrespective of its appearance on scintiscans.