The present study investigated the influence of the extent of drug effect, duration of action and dose interval on the development of acute tolerance to the respiratory and cardiovascular depressant effects of opiates. Morphine (2, 4 and 10 mg/kg i.v.) caused a dose-related reduction in heart and respiratory rates and elevation in PaCO2 which lasted 4 to 4.5 hr. Acute tolerance occurred to the effect of a second dose of 4 or 10 mg/kg but not 2 mg/kg given 4 hr after the first. When the duration of action of the opiate was limited to 75 min by injection of naloxone (0.125 mg/kg) or by the use of a short acting opiate, fentanyl (0.025 mg/kg), tolerance to a second dose of drug still developed provided it was given at least 4 hr later. When naloxone was given at the peak of the morphine effect (30 min) tolerance did not occur. It is concluded that the development of acute tolerance to opiates depends on the degree of initial drug effect and the time of receptor occupancy. The latter must be longer than that required to attain a peak response. A time period of about 4 hr appears to be necessary for the full development of the biochemical processes involved in this phenomenon.