Background: Fluorescence-based methods have been proposed to aid caries lesion detection. Summarizing and analysing findings of studies about fluorescence-based methods could clarify their real benefits. Objective: We aimed to perform a comprehensive systematic review and meta-analysis to evaluate the accuracy of fluorescence-based methods in detecting caries lesions. Data Source: Two independent reviewers searched PubMed, Embase and Scopus through June 2012 to identify papers/articles published. Other sources were checked to identify non-published literature. Study Eligibility Criteria, Participants and Diagnostic Methods: The eligibility criteria were studies that: (1) have assessed the accuracy of fluorescence-based methods of detecting caries lesions on occlusal, approximal or smooth surfaces, in both primary or permanent human teeth, in the laboratory or clinical setting; (2) have used a reference standard; and (3) have reported sufficient data relating to the sample size and the accuracy of methods. Study Appraisal and Synthesis Methods: A diagnostic 2×2 table was extracted from included studies to calculate the pooled sensitivity, specificity and overall accuracy parameters (Diagnostic Odds Ratio and Summary Receiver-Operating curve). The analyses were performed separately for each method and different characteristics of the studies. The quality of the studies and heterogeneity were also evaluated. Results: Seventy five studies met the inclusion criteria from the 434 articles initially identified. The search of the grey or non-published literature did not identify any further studies. In general, the analysis demonstrated that the fluorescence-based method tend to have similar accuracy for all types of teeth, dental surfaces or settings. There was a trend of better performance of fluorescence methods in detecting more advanced caries lesions. We also observed moderate to high heterogeneity and evidenced publication bias. Conclusions: Fluorescence-based devices have similar overall performance; however, better accuracy in detecting more advanced caries lesions has been observed.