Peri-implantitis is a biofilm-mediated inflammatory condition associated with progressive loss of supporting tissue and poses a significant challenge to clinicians worldwide. Because limited efficacy is associated with nonsurgical therapy, surgical intervention is often required to manage this disease. This article focuses on operator factors when treating peri-implantitis and presents a stepwise approach to eight essential keys for successful regenerative/reparative treatment of peri-implantitis defects. These keys are aimed at optimizing clinical outcomes for diverse patient needs and defect anatomies. They include evaluating operator experience, risk assessment, and implant restorative design, as well as nonsurgical and surgical therapies such as the use of biologics and biologic derivatives, the postoperative protocol, and a patient-specific periodontal maintenance program. By adhering to these eight keys, clinicians can achieve successful long-term outcomes in the regenerative treatment of peri-implantitis defects.