This review aims at discussing the pathogenesis of enamel fluorosis in relation to a putative linkage among ameloblastic activities, secreted enamel matrix proteins and multiple proteases, growing enamel crystals, and fluid composition, including calcium and fluoride ions. Fluoride is the most important caries-preventive agent in dentistry. In the last two decades, increasing fluoride exposure in various forms and vehicles is most likely the explanation for an increase in the prevalence of mild-to-moderate forms of dental fluorosis in many communities, not the least in those in which controlled water fluoridation has been established. The effects of fluoride on enamel formation causing dental fluorosis in man are cumulative, rather than requiring a specific threshold dose, depending on the total fluoride intake from all sources and the duration of fluoride exposure. Enamel mineralization is highly sensitive to free fluoride ions, which uniquely promote the hydrolysis of acidic precursors such as octacalcium phosphate and precipitation of fluoridated apatite crystals. Once fluoride is incorporated into enamel crystals, the ion likely affects the subsequent mineralization process by reducing the solubility of the mineral and thereby modulating the ionic composition in the fluid surrounding the mineral. In the light of evidence obtained in human and animal studies, it is now most likely that enamel hypomineralization in fluorotic teeth is due predominantly to the aberrant effects of excess fluoride on the rates at which matrix proteins break down and/or the rates at which the by-products from this degradation are withdrawn from the maturing enamel. Any interference with enamel matrix removal could yield retarding effects on the accompanying crystal growth through the maturation stages, resulting in different magnitudes of enamel porosity at the time of tooth eruption. Currently, there is no direct proof that fluoride at micromolar levels affects proliferation and differentiation of enamel organ cells. Fluoride does not seem to affect the production and secretion of enamel matrix proteins and proteases within the dose range causing dental fluorosis in man. Most likely, the fluoride uptake interferes, indirectly, with the protease activities by decreasing free Ca(2+) concentration in the mineralizing milieu. The Ca(2+)-mediated regulation of protease activities is consistent with the in situ observations that (a) enzymatic cleavages of the amelogenins take place only at slow rates through the secretory phase with the limited calcium transport and that, (b) under normal amelogenesis, the amelogenin degradation appears to be accelerated during the transitional and early maturation stages with the increased calcium transport. Since the predominant cariostatic effect of fluoride is not due to its uptake by the enamel during tooth development, it is possible to obtain extensive caries reduction without a concomitant risk of dental fluorosis. Further efforts and research are needed to settle the currently uncertain issues, e.g., the incidence, prevalence, and causes of dental or skeletal fluorosis in relation to all sources of fluoride and the appropriate dose levels and timing of fluoride exposure for prevention and control of dental fluorosis and caries.