1. The desensitization of the cholinergic receptor has been investigated at the frog neuromuscular junction. The agonist was either perfused or applied by ionophoresis.2. In all situations, desensitization develops in two phases: a fast one, experimentally in the second range but likely to be briefer, and a slower one, which extends over tens of seconds.3. When the presence of the agonist is prolonged, desensitization approaches a steady state, estimated through the amplitude of a test response. In steady-state conditions, this amplitude depends upon the desensitizing agonist concentration. The dose-response curve for desensitization induced by carbachol (CCh) indicates that half of the receptors can be desensitized at room temperature in the presence of 2.3 mum-CCh. The shape of the curve suggests that one desensitized receptor can bind two CCh molecules.4. The recovery from desensitization, estimated with a repetitive test pulse, displays two exponential phases. The time constant of the fast phase is 11-12 sec, and 4-5 min for the slow phase, regardless of the concentration or the nature of the agonist (acetylcholine or carbachol).5. The factor which most strikingly affects the relative amplitudes of the fast and slow phases of recovery is the duration of the (desensitizing) agonist application. Desensitizations lasting a few seconds are followed by a ;fast' recovery, whereas the slow phase of recovery is prominent when the agonist has been applied for more than 2 min.6. The fast and slow phases of desensitization onset and offset are not due to independent causes but are coupled: in given conditions, the onset can be essentially fast, and the recovery slow.7. All our findings can fit in a cyclic scheme of desensitization, derived from the one of Katz & Thesleff (1957) with two modifications: whether activatable or desensitized, one receptor molecule would have two agonist binding sites; moreover, the desensitized receptor would exist in two distinct and interconverting conformations: D(1), giving rise to the fast phases of onset and offset, and D(2), responsible for the existence of the slow components of desensitization.