Caffeine and amphetamine have been regarded as dramatically dissimilar drugs, both structurally and behaviorally. However, both are stimulants and (under certain conditions) both produce self-injurious behavior in rats which is potentiated by clonidine. Rats were pretreated with various doses of clonidine prior to daily administration of caffeine. In another experiment, rats which had been implanted with continuous release amphetamine pellets were injected twice daily with various doses of clonidine. Clonidine produced a high rate of self-biting when combined with subthreshold doses of caffeine. Clonidine was less effective in potentiating amphetamine induced self-biting; the highest dose tested raised the incidence from 28 to 64%. Clonidine tended to decrease the incidence of behaviors other than self-biting. Thus although caffeine and amphetamine clearly do not have identical behavioral effects, there is increasing evidence that certain of their effects are mediated by similar mechanisms.