Rats received either cis-flupenthixol (0.8–1.2 mg/kg per day) or trans-flupenthixol (0.9–1.2mg/kg per day) continuously in drinking water for periods up to 18 months. cis-Flupenthixol, but not trans-flupenthixol, initially inhibited apomorphine-induced stereotyped behaviour but by 6 months and thereafter the stereotyped response was enhanced compared to age-matched control animals. Striatal and mesolimbic homovanillic acid and 3,4-dihydroxyphenylacetic acid concentrations were elevated for up to 3 months after starting cis-, but not trans-flupenthixol intake, but thereafter levels generally fell below those for age-matched control animals. Dopamine concentrations were not altered by cis- or trans-flupenthixol administration. The number of striatal [ 3H]spiperone binding sites ( B max ) was decreased by 40% after 1 months' administration of cis-flupenthixol but this gradually reversed, such that by 18 months a 40% increase in B max was apparent. Administration of trans-flupenthixol decreased B max up to 3 months but thereafter values were not different from those found in age-matched control animals. The dissociation constant ( K D ) for [ 3H]spiperone binding in striatum was not altered by 6 months cis-flupenthixol intake, but then increased as drug administration continued. trans-Flupenthixol administration did not alter striatal K D values. B max for [ 3H]spiperone binding to mesolimbic preparations was not altered by up to 12 months cis-flupenthixol intake, but was decreased after 18 months drug administration. cis-Flupenthixol administration had no effect on mesolimbic K D values. Administration of trans-flupenthixol for up to 18 months did not alter mesolimbic B max or K D values for [ 3H]spiperone binding. Dopamine (50 μM)-stimulation of striatal adenylate cyclase was inhibited up to 3 months cis-, but not trans-flupenthixol administration, but thereafter was not different from control values. In mesolimbic tissue cis-flupenthixol inhibited adenylate cyclase activity for up to 6 months but then values were not different from those for control animals, trans-Flupenthixol inhibited adenylate cyclase activity after 1 month, but from then on, values were not different from control levels. Continuous chronic administration of the isomers of flupenthixol causes a stereoselective reversal of the initial dopamine receptor blockade caused by cis-flupenthixol so as to produce striatal dopamine receptor supersensitivity. In mesolimbic tissue reversal of initial receptor blockade also occurred but no evidence for increased dopamine receptor function was obtained. These findings may be of relevance to the mode of action of antipsychotic drugs or to the mechanism by which tardive dyskinesias are produced in man.