There is evidence that drug-associated exteroceptive cues elicit compensatory conditional responses (CCRs) that contribute to tolerance. The authors evaluated whether interoceptive, self-administration cues (SACs) similarly contribute to tolerance. In Experiments 1 and 2, the ataxic effect of ethanol was measured in rats that self-administered (SA) ethanol--by either oral consumption or intragastric infusion--and in rats that were yoked (Y) to these self-administrators. In both experiments, the ataxic effect of ethanol was more pronounced in Y than in SA rats. In addition, SA rats failed to display usual levels of tolerance when ethanol was administered in the absence of SACs and displayed a CCR of hypertaxia in response to SACs not followed by ethanol. The results of Experiment 3 indicate that the ataxic effect of intravenous heroin also was greater in Y than in SA rats. The findings suggest that SACs contribute to drug tolerance.