Multinucleated giant cells (MNGCs) are a special class of giant cell formed by the fusion of monocytes/macrophages abundantly found in human tissues. While historically their role around certain classes of biomaterials have been directly linked to a foreign body reaction leading to material rejection, recent accumulating evidence has put into question their role around certain classes of bone biomaterials. It was once thought that specifically in bone tissues, all giant cells were considered osteoclasts characterized by their ability to resorb and replace bone grafts with newly formed native bone. More recently, however, a special subclass of bone biomaterials has been found bordered by large MNGCs virtually incapable of resorbing bone substitutes even years after their implantation yet surrounded by stable bone. Interestingly, research from the field of cardiovascular disease has further shown how a shift in macrophage polarization from M1 "tissue-inflammatory" macrophages toward M2 "wound-healing" macrophages in atherosclerotic plaque may lead to MNGC formation and ectopic calcification of arteries. Despite the growing observation that MNGC formation occurs around certain bone biomaterials, their role in these tissues remains extremely poorly understood and characterized. In summary, four central aspects of this review are discussed with a focus on (1) the role of MNGCs in bone/tissue biology, and their ability to induce vascularization/new bone formation, their role around, (2) bone substitutes for bone augmentation, (3) dental implants, as well as (4) during peri-implant infection. The authors express the necessity to no longer refer to MNGCs as "good" or "bad" cells, but instead point toward the necessity to more specifically characterize them scientifically and appropriately as M1-MNGC and M2-MNGC accordingly. Future research investigating the factors influencing their polarization as a "center of control" is also likely to act as a key factor in the progression/resolution of various diseases.