Clinical trials, animal studies, and in vitro tests demonstrate effectiveness of exposure to topical (posteruptive) fluoride in caries prevention and reduction of enamel dissolution. However, careful analyses of human epidemiologic data on caries increments, following communal water fluoridation, show unquestionably that fluoride has an important preemptive effect on caries in permanent teeth, particularly on pit and fissure surfaces. These preemptive or systemic benefits also apply to the use of fluoride supplements or fluoridated salt when used continuously during the period of tooth formation. The role of systemic fluoride in caries prevention is neither “minimal” nor “of borderline significance.” On the contrary, it is a major factor in preventing pit and fissure caries, the most common site of tooth decay. Maximal caries-preventive effects of water fluoridation are achieved by exposure to optimal fluoride levels both pre- and posteruptively.