This paper reviews the use of intra-oral model systems to help elucidate the role of fluoride and its mechanism of action in caries prevention. The intra-oral models currently in use were found to be of three general types. The most widely used system has consisted of a removable appliance that relies on the use of dacron gauze or a recessed sample to enhance plaque formation. Similarly, the banding model of Ogaard requires the presence of orthodontic band material to produce a plaque accumulation niche for demineralization, while the crown single-section technique relies mainly on placement of the sections in plaque-retentive areas (below contact points). In general, the models may be used for the assessment of food cariogenicity, an evaluation of de- and re-mineralization, and measurement of fluoride incorporation into enamel or root substrates. On evaluation of lesion initiation and progression in vivo, it is apparent that few non-destructive in vivo techniques are available that offer the sensitivity of laboratory-based analysis. Thus, the use of intra-oral models that allow lesion formation and progression to occur in the oral environment, but can be measured with the sensitivity of in vitro techniques, has been extremely important. Although the magnitude of the fluoride dose, the longevity of fluoride in the oral environment, and the time required for remineralization are different from those found in vitro, it is apparent that the presence of fluoride in the aqueous phase is now thought to be of primary importance. Mechanistically, the presence of fluoride will both inhibit demineralization by acid and promote remineralization under more neutral conditions. Thus, one of fluoride's major contributions is to affect the rates of lesion formation and progression. It was concluded that low-concentration fluoride agents with a high frequency of application would best fulfill the above needs.