Many scientific data show that periodontal regeneration is an effective and predictable procedure for the treatment of isolated and multiple intrabony defects. Meta-analyses from systematic reviews show a clinical advantage in terms of clinical attachment level gain when demineralized freeze dried bone allograft, barrier membranes and amelogenins are applied in comparison with open flap debridement alone. On the other hand, a consistent amount of variability of the outcomes is evident among different studies and within the experimental population of the same study. This variability is explained, at least in part, by the different patient and defect characteristics and by a different degree of skill of the surgeon. Patient-related factors are smoking habit, compliance with home oral hygiene and residual inflammation after cause-related therapy. Defect-associated factors include defect depth and Rx angle, number of residual bony walls, pocket depth, and the degree of hypermobility. Surgical skill and experience to manipulate the delicate papilla preservation techniques is required along with the knowledge of indication and limits of the different regenerative materials. A strategy to optimise the surgical design of the flap, the use of the regenerative materials according to their characteristics, and the application of passive sutures is presented in this review, along with the foundation of the scientific background.