Fluoride appears to specifically interact with mineralizing tissues, causing an alteration of the mineralization process. In enamel, fluorosis results in a subsurface hypomineralization. This hypomineralized enamel appears to be directly related to a delay in the removal of amelogenins at the early-maturation stage of enamel formation. The specific cause for this delay is not known, although existing evidence points to reduced proteolytic activity of proteinases that hydrolyze amelogenin. This delay in hydrolysis of amelogenins could be due to a direct effect of fluoride on proteinase secretion or proteolytic activity, or to a reduced effectiveness of the proteinase due to other changes in the protein or mineral of the fluorosed enamel matrix. The formation of dental fluorosis is highly dependent on the dose, duration, and timing of fluoride exposure. The early-maturation stage of enamel formation appears to be particularly sensitive to the effects of fluoride on enamel formation. Although the risk of enamel fluorosis is minimal with exposure only during the secretory stage, this risk is greatest when exposure occurs in both secretory and maturation stages of enamel formation. The risk of fluorosis appears to be best related to the total cumulative fluoride exposure to the developing dentition.