The caries-preventive effect of fluoride is mainly attributed to the effects on demineralization/remineralization at the tooth oral fluids interface. Sub ppm levels of fluoride in saliva are effective in shifting the balance from demineralization, leading to caries, to remineralization. This is attributed to the fluoride-enhanced precipitation of calcium phosphates, and the formation of fluorhydroxyapatite in the dental tissues. Low fluoride levels are found in saliva after toothbrushing with fluoride containing dentifrices. Similar concentrations are ineffective in interfering with processes of growth and metabolism of bacteria, and also do not result in a significantly reduced dissolution of tooth mineral as a result of (firmly bound) fluoride incorporation. Comparative studies of fluoride efficacy have shown that higher concentrations in solution are needed in pH-cycling studies of dentine than in enamel to maintain the mineral balance or to induce remineralization. This is attributed to the greater solubility of the dentine and the smaller size of the dentine crystallites compared to enamel. Fluoride slow-release devices, in the form of fluoride-releasing restorative materials, may serve to increase the fluoride levels in saliva and plaque to levels at which caries can be prevented, also in high-risk patients. Research questions for the next millennium and future perspectives for fluoride applications should be found in the retention and slow release of fluoride after various combinations of fluoride treatment, the combination of fluoride and anti-microbial treatment, the individualization of caries prevention, and the combination of preventive schemes with new developments in caries diagnosis.