Hypothermia and motor impairment (tilt-plane test) were used to assess the phenomenon of rapid cross-tolerance between ethanol and pentobarbital in rats. The hypothermic and motor-impairment responses were significantly reduced on day 2 in animals receiving ethanol on day 1, compared to the control group pretreated with saline. Ethanol pretreatment, however, did not result in rapid cross-tolerance to pentobarbital on either test. Pentobarbital pretreatment on day 1 resulted in rapid tolerance to pentobarbital on day 2. However, in contrast to the lack of rapid cross-tolerance to pentobarbital after pretreatment with ethanol, pentobarbital pretreatment clearly conferred rapid cross-tolerance to ethanol. Determination of ethanol and pentobarbital blood levels suggested that pharmacokinetic alterations did not contribute significantly to the observed rapid tolerance and cross-tolerance. The asymmetry of rapid cross-tolerance seen in these studies mimics the results obtained by us in chronic tolerance and cross-tolerance studies reported recently. These results suggest that rapid tolerance and cross-tolerance can be used as predictors of chronic tolerance and cross-tolerance.