Purpose: The use of biologic agents is emerging in bone regeneration procedures due to their ability to increase cellular events in wound healing and therefore to obtain more predictable outcomes. Hence, the aim of the present study was to critically evaluate the methodology of systematic reviews investigating biologic agents in promoting bone formation and implant site development. Materials and Methods: A literature search for systematic reviews with and without meta-analyses was performed in Medline, Embase, and the Cochrane database, as well as in journals with high impact factors in periodontics and implant dentistry. Titles, abstracts, and full-text articles were analyzed for potential inclusion. Three guidelines-AMSTAR, R-AMSTAR, and the checklist proposed by Glenny et al-were utilized to analyze their methodologic quality. Two calibrated reviewers performed all data extraction and appraisal. Cohen's kappa coefficients were calculated to appraise the interexaminer agreement. Results: A total of 12 systematic reviews, 3 with meta-analyses, were evaluated. Platelet-rich derivatives and BMP-2 were the most widely studied biologic agents and sinus augmentation was the most common procedure evaluated. The R-AMSTAR mean score was 28 (range 14-38) and none of the systematic reviews analyzed met all of the items. In the AMSTAR checklist, the mean score was 5.75 (range 2-9) and the only item met by all the systematic reviews was the a priori design. The Glenny et al checklist mean score was 8.6 (range 4-13) and two items, "focused question" and "to identify all relevant studies," were met by all systematic reviews. Conclusion: Systematic reviews on biologic agents to promote bone formation at implant site development demonstrate substantial methodologic variability. Therefore, caution must be exercised when interpreting their findings.