Large individual differences exist among mice in their behavioral responses to drugs of abuse, and many of these differences have a substantial genetic basis. The creation of new animal models using recombinant DNA technology has provided new genetic tools for assessing the role of specific candidate genes in drug response. This study presents a characterization of cocaine activation and reward in the two strains used most commonly for production of knockout mice, C57BL/6J and 129/SvJ, and their outcrossed F1 offspring. Using conditioned place preference, the study demonstrates that there are large strain differences in spontaneous locomotor activity and in the rewarding effects of cocaine. The 129/SvJ strain is hypoactive and is very sensitive to the locomotor activating effects of cocaine but does not develop cocaine-conditioned place preference under conditions that yield significant place preference in C57BL/6J mice. These phenotypes are not inherited in a simple additive manner, but rather the F1 generation resembles the C57BL/6J progenitor strain for a number of the behaviors examined.