Sensitization to the psychostimulant effects of cocaine has received widespread attention because concomitant changes occur in neurochemical pathways that are part of the brain reward pathway. The current study was undertaken with the purpose of mapping genes determining sensitivity to the acute stimulant and sensitizing effects of cocaine. Sensitivity and sensitization to cocaine (5, 10, and 40 mg/kg) were measured in 25 BXD/Ty recombinant inbred (BXD RI) strains and the progenitor C57BL/6J (B6) and DBA/2J (D2) strains. Quantitative trait locus (QTL) mapping provisionally localized cocaine sensitivity genes to regions on all chromosomes except 6, 11, 17, and X; sensitization QTLs were localized to chromosomes 1-10, 13, 15, 18, 19, and X. Provisional QTLs for locomotion after saline injection in a novel setting were mapped to chromosomes 1, 3-6, 9, 12, 13, 18, and 19 and in a familiar setting to chromosomes 4-7, 9, 13, and 19. There were both common and unique QTL regions across the phenotypes. Evidence for a genetic association between magnitude of acute cocaine response and sensitization was obtained for only the 10 mg/kg dose. Some common QTL regions for cocaine, ethanol, and methamphetamine responses suggest the possibility that these drugs induce stimulant effects or sensitization through some common mechanisms. However, independent mechanisms were also indicated. Many candidate genes reside near the provisional QTLs mapped for cocaine responses, including genes coding a variety of neurotransmitter and hormone receptors. These data, once confirmed, should prove useful for directing investigations of acute and chronic cocaine effects down already suspected and novel avenues.