Rats made thyrotoxic with large doses of thyroxine (T4) during the neonatal period (neo-T4) show many abnormalities as adults. These usually include impaired body, pituitary and thyroid growth, diminished pituitary and serum TSH concentrations, a diminished serum T4 and a diminished response to PTU challenge and to thyrotropin-releasing hormone (TRH) stimulation. Experiments are presented which show that these rats are hypersensitive to feedback regulation by T4 in a manner similar to that seen after bilateral anterior hypothalamic lesions. They show a subnormal response to PTU challenge and an excessive suppression of serum TSH and goiter growth after T4. Pituitary TSH was less depleted in neo-T4 rats when a small dose of T4 was given daily with PTU and pituitary TSH was more sensitive to suppression by a larger dose of T4 in the neo-T4 group. There was an impaired rebound increase in pituitary TSH following a single inhibitory dose of T4 injected into the adult hypothyroid rat. Although the hypothalamic TRH content is increased in the neo-T4 rat, the circulating concentration of TRH was found to be significantly decreased, supporting the theory that the defects observed in the neo-T4 rat may be the consequence of an impaired hypothalamic secretion of TRH.