Repeated administration of cocaine to B6AF1/J mice increased their running response to 20 mg/kg cocaine as much as four-fold over the response to the first injection. After four daily injections, the extent of the increase was proportional to the dose of cocaine that was used for pretreatment. Sensitization persisted for as long as 2 months after the last injection of cocaine. Cocaine-pretreated mice did not show an increased running response to either morphine or d-amphetamine. The response to cocaine was increased two-fold by treatment with morphine and three-fold by pretreatment with d-amphetamine. Pretreatment with either imipramine or reserpine did not produce sensitization to cocaine. There was no correlation between cocaine sensitization and whole-brain catecholamine levels. There were marked differences in both the running response to cocaine and the extent of cocaine sensitization betwee the parental strains, C57B1/6J and A/J. Experiments with recombinant-inbred lines, derived from C57B1/6By and BALB/cBy mice, suggest that the initial response to cocaine and the development of sensitization are controlled by different genetic determinants.