Gene-targeting techniques to produce null mutations provide a powerful method for evaluating the contribution of particular candidate genes involved in motivation. The embryonic stem cell lines in which homologous recombination is undertaken are derived from 129 mice, but because of the impoverished performance of 129 mice on a number of behavioral tasks, mice chimeric for the mutation are often bred with a C57BL/6 mouse strain. Thus, an examination of both parental strains is important in the study of the knock-out mice. Although the C57BL/6 behavioral phenotype is well documented, details of the 129 phenotype have not been the focus of study until recently. We investigated opiate motivation in both 129/SvJ and C57BL/6J mouse strains to determine whether, and under what circumstances, the 129/SvJ mouse exhibited motivated behavior toward opiates. 129/SvJ mice required both drug and contextual cues to demonstrate morphine conditioned place preferences on test day, whereas C57BL/6J mice required only contextual cues to express opiate place conditioning. Pentobarbital and diazepam but not saline, cocaine, or naloxone could substitute for morphine on test day in 129/SvJ mice, demonstrating that morphine indeed has rewarding motivational valence in the 129/SvJ mouse strain. This critical, interoceptive cue in 129/SvJ mice on test day may be the anxiolytic properties of the effective drugs. Therefore, some deficits observed in 129 mice and mice harboring this genetic background may be attributed to high levels of anxiety during the retrieval period rather than to sensory, learning, or motivational deficits.