Dose-effect curves were determined for the effects of drugs on responding under a multiple fixed-ratio 10-response fixed-interval 90-sec schedule of food presentation before and during chronic exposure to drugs in the drinking water. In rats consuming 70 to 90 mg/kg of morphine per day, the dose-effect curves for the rate-decreasing effects of morphine on responding under both schedule components shifted 1/2 log unit to the right, but the dose-effect curves for methadone, pentobarbital and d-amphetamine showed little change. In rats consuming 30 to 55 mg/kg of methadone per day there was little change in the dose-effect curves for the rate-decreasing effects of methadone and d-amphetamine on responding, but the dose-effect curve for morphine shifted 1/2 log unit to the right and the dose-effect curve for pentobarbital shifted upward and to the right. In rats consuming 40 to 50 mg/kg of pentobarbital per day, the dose-effect curve for the rate-decreasing effects of pentobarbital shifted to the right by about 1/4 log unit, and there was a similar but less marked shift to the methadone dose-effect curve to the right. In rats consuming pentobarbital, the morphine dose-effect curve was little changed. These experiments suggest that chronic methadone consumption confers greater tolerance to the effects of morphine on schedule-controlled behavior than it confers upon itself, while chronic morphine consumption confers greater tolerance to its own behavioral effects than it does to those of methadone. There appears to be some reciprocal cross-tolerance between methadone and pentobarbital for schedule-controlled behavior, but not between morphine and pentobarbital.