Objective: To evaluate the relationship between genetic polymorphism and external apical root resorption. Methodology: The protocol was prepared and registered on PROSPERO. Two reviewers independently conducted a comprehensive literature search. The MEDLINE, Embase, Cochrane, and PubMed databases were searched. In addition, the bibliographies of all relevant articles and textbooks were manually searched. Results: Thirteen studies met the inclusion criteria. Four studies were classified as low-quality studies (score ,10), and nine studies were classified as high-quality studies. Discussion: The results of the present review suggest that, although some authors have reported that genetic polymorphism may play a role in external apical root resorption, others have not supported this association. Future studies should be more consistent in their research methodologies to determine with clarity whether an association exists. Conclusion: Future investigations should include larger sample sizes with matching cases/ controls, adjust for confounders, provide power calculation and odds ratios, and report genetic analyses with the Hardy-Weinberg equilibrium. The current investigation suggests guidelines and recommendations for future investigators studying genetic polymorphism in patients undergoing orthodontic treatment. (Angle Orthod. 2016;86:1042-1049