1. Chloroethylclonidine (CEC) has an affinity for all 6 subtypes of alpha-adrenoceptor, but binds irreversibly particularly to alpha 1B-, alpha 1D-, alpha 2C-, and alpha 2A/D-adrenoceptors. 2. Functionally, CEC behaves as an irreversible alpha 1-adrenoceptor antagonist, reducing the maximum response to noradrenaline (NA), and shows subtype selectivity in that alpha 1A-adrenoceptors are relatively insensitive to CEC. CEC also behaves as an irreversible alpha 2-adrenoceptor agonist, both prejunctionally in the rat vas deferens and postjunctionally in the dog saphenous vein. 3. In the rat aorta, CEC does not produce direct contractions, but following exposure to CEC concentrations of NA of 10 microM and above produce contractions resistant to alpha 1- and alpha 2-adrenoceptor blockade. We have investigated this phenomenon in detail. 4. Receptor protection experiments were carried out in the rat aorta, in which the protecting agent was present prior to and during exposure to CEC. The component of the contraction to NA resistant to alpha-blockade was still present following receptor protection with the alpha 1-adrenoceptor antagonist prazosin, but absent following receptor protection with NA and reduced following receptor protection with alpha 2-adrenoceptor antagonists. The resistant response may represent an irreversible agonist interaction between CEC, NA, and normally silent alpha 2-adrenoceptors, that cannot be affected by subsequent competitive antagonism, but that can be prevented by receptor protection with the agonist NA prior to CEC. 5. CEC has two major classes of action at alpha-adrenoceptors: irreversible antagonism at alpha 1-adrenoceptors, and irreversible agonism at alpha 2-adrenoceptors. Both actions can be demonstrated in the rat aorta.