Pharmacological selectivity of tolerance to the discriminative stimulus effects of morphine or d-amphetamine was examined in pigeons trained to discriminate among 3.2 mg/kg morphine, saline, and 1.8 mg/kg d-amphetamine under a 3-key fixed-ratio 30 schedule of food delivery. Cumulative doses of morphine (0.32-10 mg/kg) or d-amphetamine (0.10-3.2 mg/kg) evoked morphine- or d-amphetamine-key responding, respectively, in a dose-dependent manner. Suspending training and administering repeated doses of morphine (32 mg/kg b.i.d.) for 1 week increased the dose of morphine required for morphine-key responding approximately 5-fold, without altering sensitivity to d-amphetamine. Conversely, repeated treatment with d-amphetamine (5.6 mg/kg b.i.d.) increased the dose of d-amphetamine required for d-amphetamine-key responding approximately 7-fold, without decreasing sensitivity to morphine. Repeated treatment with saline (1 ml/kg b.i.d.) for 1 or 2 weeks did not alter sensitivity to stimulus effects of either morphine or d-amphetamine. Sensitivity to stimulus effects of morphine recovered fully within 1 week after morphine treatment ended; sensitivity to stimulus effects of d-amphetamine recovered partially within 3 days after d-amphetamine treatment ended. For morphine, but not for d-amphetamine, increases in the dose required for stimulus effects were accompanied by increases in the dose required for rate-reducing effects. These results demonstrate that tolerance to discriminative stimulus effects of morphine and d-amphetamine is pharmacologically selective and suggest that pharmacotherapies targeted to one drug of abuse may produce little change in sensitivity to subjective effects of drugs from a different pharmacological class.