Continuous administration of trifluoperazine (2.5–3.5 mg/kg/day) or thioridazine (30–40 mg/kg/day) to rats for 12 months enhanced the stereotyped response to apomorphine (0.5 mg/kg sc.), increased dopamine (1–150 μM) stimulation adenylate cyclase, increased KD and Bmax for dopamine (10−4 M) specific 3H-spiperone striatal binding and produced spontaneous mouthing movements. On drug withdrawal, spontaneous locomotor acitivity was enhenced after 2 weeks and the enhanced stereotyped response was maintained for up to 1 month. Spontaneous mouthing had disappeared 2 weeks after drug withdrawal. The increase in Bmax for 3H-spiperone binding was maintained for up to 3 months after drug removal, but KD reverted to control levels by 2 weeks. In contrast, the dopamine stimulation of striatal adenylated cyclase remained enhanced for the 6 month withdrawal period. Administration of trifluoperazine (0.7–0.9 mg/kg/day) or thioridazine (6–8 mg/kg/day) for 12 months produced a less marked effect than administration of the higher dose. No enhancement of effect was observed on drug withdrawal and the initial changes disappeared rapidly on removal of drug. Supersensitivity of striatal dopamine mechanims produced by continuous long-term neuroleptic administration differs from that produced by shorted treatment periods since no enhancement of effect occurs on drug withdrawal. The behavioural and biochemical components of the supersensitivity show variable time courses and in particular the enhanced stimulation of striatal adenylate cyclase persists for at least 6 months. Such effects may be of relevance to tardive dyskinesias in man.