Endodontic and periodontal microsurgery has surpassed the success rates for traditional endodontic and periodontal surgical procedures. Excellent healing results are being attributed to both the techniques, when employed, for isolated endodontic or periodontal defects. Combined endodontic-periodontal lesions have been referred to as a true challenge, requiring not only endodontic microsurgical management but also concurrent bone grafting and membrane barriers techniques. The prevention of epithelial downgrowth and regeneration of periodontal cementum, fiber, and bone seals the fate of these cases. Achieving primary closure with submergence of grafts has a positive effect on GTR outcome. New techniques of periodontal microsurgery, such as minimally invasive papilla preserving flaps with passive internal mattress suturing, have managed to obtain 90% primary flap closure over grafted sites. Root surface treatment and conditioning has also shown to be beneficial for GTR. Endodontic microsurgery for the combined lesion has not integrated these advances yet. These advances, along with a recently suggested treatment strategy, are ushering in the level next in management of the combined lesions. This article offers an overview of the combined lesion, the disease, its classification, treatment strategy, regenerative tools, microsurgical recommendations, and outcome studies.