Macrophages are the most versatile, plastic, and mobile cells in the animal kingdom. They are present in all tissues and might even define a true " body-wide" network that maintains health and ensures the repair of tissues and organs. In specific and rare instances, macrophages fuse to form multinucleate osteoclasts and giant cells in bone and in chronic inflammatory reactions, respectively. While macrophages lose most of their plasticity and mobility after they become multinucleate, at the same time they acquire the capacity to resorb calcified tissues, such as bone, and foreign bodies, such as pathogens and implants, and they mediate the replacement of the resorbed tissue by new tissue. There is evidence to suggest that macrophages might also fuse with somatic cells to repair tissues and with tumor cells to trigger the metastatic process. The molecular machinery of macrophage fusion remains poorly characterized, but it is likely to be shared by all fusing macrophages.