Investigation of environmental influences on phenotypic expression of diverse genotypes may provide insight into genetic vulnerability to disease and genomic factors involved in the stress response. The studies presented use null mutant technology to begin to provide insight into these gene-environment interactions. Specifically, these studies present evidence that environmental stress has a significant effect on learning and memory, locomotion, and neurochemistry which is modulated by genetic background strain and the presence of specific proteins. Across the experiments, 14-days of daily restraint stress generally enhanced both object recognition performance and radial arm maze and had minor if any effects on open field activity or neurotransmitter levels. Notably, significant differences in baseline behavioral performance and neurotransmitter levels between background strains was observed. In addition, this collection of studies has found that calbindin-D28k is an important protein in mediating stress effects on learning and memory and that lack of calbindin-D 28k diminished the ability of the system to counteract harmful effects of stress. Alternately, results from these studies do not indicate that COMT plays a significant role in mediating stress effects on learning or memory. What was revealed in the COMT studies, however, was the importance of background strain in expression of the null mutation. Results presented discuss the implications of these findings relevant to current knowledge of genetic differences, gene-environment interactions, and stress mechanisms.