Concurrent with the decline in dental caries has been an increase in the prevalence of dental fluorosis, a side-effect of exposure to greater than optimal levels of fluoride during amelogenesis. The mechanisms that underlie the pathogenesis of dental fluorosis are not known. We hypothesize that genetic determinants influence an individual's susceptibility or resistance to develop dental fluorosis. We tested this hypothesis using a mouse model system (continuous eruption of the incisors) where genotype, age, gender, food, housing, and drinking water fluoride level can be rigorously controlled. Examination of 12 inbred strains of mice showed differences in dental fluorosis susceptibility/resistance. The A/J mouse strain is highly susceptible, with a rapid onset and severe development of dental fluorosis compared with that in the other strains tested, whereas the 129P3/J mouse strain is least affected, with minimal dental fluorosis. These observations support the contribution of a genetic component in the pathogenesis of dental fluorosis.