Regenerative periodontal therapy aims to form new cementum, periodontal ligament, and alveolar bone, all sealed by gingival tissue. The root surface acts as the wound margin during this regeneration process. Root surface biomodification (root conditioning/root decontamination), therefore, seems instrumental in promoting surface decontamination and enhancing tissue attachment by removing the smear layer, exposing collagen fibrils, and facilitating blood clot formation and stabilization. This review attempted to provide an all‐encompassing, evidence‐based assessment of the role of root surface biomodification in regenerative periodontal therapy, particularly in intrabony defects, furcation defects, and root coverage procedures. The reviewed evidence suggested that root conditioning agents, whether used independently or in conjunction with bone graft materials, biological agents, membranes, or connective tissue grafts, do not offer any clinical advantage regarding clinical attachment gain. Thus, integrating chemical methods with the mechanical root instrumentation process does not necessarily contribute to superior clinical outcomes.