The interrelationship between periodontal and endodontic disease has aroused much speculation, confusion, and controversy. Pulpal and periodontal problems are responsible for more than 50% of tooth mortality today. Diagnosis is often difficult since these diseases have been studied primarily as separate entities. The toxic substances of the pulp may initiate periodontal defects through canal ramifications and patent dentinal tubules, thus impairing wound healing in regenerative procedures. Although no studies exist addressing the direct effect of pulpal infection on the outcome of guided tissue regeneration (GTR) procedures, several studies do indicate that pulpal status may play a significant role toward the end results of GTR. This review article discusses the potential influence of endodontic treatment on the long-term outcomes of GTR. Potential pathways between the pulp and periodontal ligament, which may be responsible for the failure of the regeneration of new periodontal attachment apparatus, are explored. Examination and review of the clinical and research findings in the literature relating to perio-endo lesions are made to demonstrate that a negative influence may exist between GTR outcomes and the status of the pulp.