The evidence is reviewed that a desensitization to thyrotropin is of three distinct types. Type 1 is proximal to the production of cyclic AMP and is manifested by a fall of cyclic AMP concentration in the thyroid tissue despite the continued presence of TSH or phosphodiesterase inhibitors in the medium. Type 2 is distal to this event and involves the metabolic effects of TSH mediated by cyclic AMP such as colloid droplet formation, iodide organification and, in dog thyroid, glucose oxidation. All these effects may be due to a reduced amount of cyclic AMP which is not capable of stimulation the protein kinase. They may be prevented by a pre-exposure to similar concentrations of TSH and cannot be overcome by other stimulators acting through the same adenylate cyclase-cyclic AMP pathway. Type 3 involves the processes not regulated by cyclic AMP. Thus, a desensitization of thyroid tissue by pre-exposure to TSH results in a reduced response of phospholipid turnover, a process not mediated by cyclic AMP, either to homologous (TSH) or heterologous (acetylcholine) stimulation.