Genetic strains of mice represent an important resource for research on the biological determinants of complex diseases and behavioral phenotypes. To date, the approaches used have had little success in identifying causal genes. We have evaluated brain gene expression in C57BL/6J (B6) and DBA/2J (D2) inbred mouse strains using differential display to identify a number of sequences showing significant expression differences between the two strains. These differences were confirmed by semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) and real-time PCR. Knowing that B6 and D2 mouse strains differ for a number of behavioral phenotypes, we asked whether this difference in brain gene expression could explain any of these traits. Here, we show that the expression of two of these genes, retinaldehyde binding protein 1 (Rlbp1) and syntaxin 12 (Stx12), co-segregate with the ethanol preference phenotype in a B6D2 F2 population. Our results suggest a potential role for Rlbp1 and Stx12 in ethanol preference in mice, a conclusion supported by the location of these genes in quantitative trait loci (QTL) regions for this phenotype. This experimental approach has the potential for a broad application in the assessment of the roles of differentially expressed genes in a variety of complex phenotypes, with the advantage of identifying novel and potentially causal candidate genes directly.