An investigation of the periodontal literature reveals four critical factors necessary for a regenerative response in the treatment of intrabony defects. These include root preparation to remove toxins and altered cementum, space creation by the graft or membrane barrier for migration of progenitor cells, stabilization and flap coverage of the graft, and use of a membrane barrier or enamel matrix derivative (EMD). This article reviews the literature supporting this concept and presents a clinical decision tree to determine when to use EMD alone or with autogenous grafts and membrane barriers in the treatment of defects of varying morphologies. The clinical decision tree is designed to increase the predictability of a positive clinical response. Cases are shown to demonstrate the indication for each treatment.