The purpose of this study was to identify genetic factors that contribute to dental caries susceptibility, either alone or in combination with environmental factors. Dental examinations were performed and buccal swab samples collected from 3- to 5-year-old children with at least 4 surfaces of decay, or with no evidence of decay. SNP assays for each of 6 candidate genes were performed for all cases and controls. Chi-square analysis and regression analysis were used for the evaluation of individual gene effects, environmental effects, and gene-environment interactions. There were no significant associations between single candidate genes and caries susceptibility. Levels of S. mutans were positively and Lactobacilli were negatively associated with caries. Regression analysis revealed a significant interaction between tuftelin and S. mutans, with 26.8% of the variation in dmfs explained by the interaction. Future research will focus on the identification of these additional factors and the development of functional assays so that these interactions can be better understood.