Fluoride gels have been widely used since the 1970s. The aim of this review was to assess the effectiveness and safety of fluoride gels in the prevention of dental caries in children and to examine factors potentially modifying their effectiveness. Relevant randomized or quasi-randomized trials were identified without language restrictions by searching multiple databases, reference lists of articles, and journals and by contacting selected authors and manufacturers. Trials with blind outcome assessment comparing fluoride gel with placebo or no treatment for at least one year and involving children under seventeen years of age were selected. Inclusion decisions, quality assessment, and data extraction were duplicated in a random sample of one third of studies, and consensus was achieved by discussion or a third party. Random effects meta-analyses were performed where data could be pooled. Potential sources of heterogeneity were examined in random effects meta-regression analyses. The main outcome was caries increment measured by the change in decayed, missing, and filled permanent tooth surfaces (D(M)FS). The primary measure of effect was the prevented fraction (PF) that is the difference in mean caries increment between the treatment and control groups expressed as a percentage of the mean increment in the control group. Potential adverse effects and unacceptability of treatment were also recorded. Twenty-five studies were included, involving 7,747 children. For the twenty-three that contributed data for meta-analysis, the D(M)FS pooled prevented fraction estimate was 28 percent (95 percent CI, 19 percent to 37 percent; p < 0.0001). There was clear heterogeneity, confirmed statistically (p < 0.0001). The effect of fluoride gel varied according to type of control group used, with D(M)FS PF on average being 19 percent (95 percent CI, 5 percent to 33 percent; p < 0.009) higher in non-placebo controlled trials. Only two trials reported on adverse events. There is clear evidence of a caries-inhibiting effect of fluoride gel. The best estimate of the magnitude of this effect, based on the fourteen placebo-controlled trials, is a 21 percent reduction (95 percent CI, 14 to 28 percent) in D(M)FS. This corresponds to an NNT of two (95 percent CI, 1 to 3) to avoid one D(M)FS in a population with a caries increment of 2.2 D(M)FS/year, or an NNT of twenty-four (95 percent CI, 18 to 36) based on an increment of 0.2 D(M)FS/year. However, further work is needed to identify and quantify potential harmful effects of fluoride gels.