Macrophagal polykaryocytes (MPs) are terminally differentiated multinuclear macrophage cells responsible for remodeling and resorption of bone, foreign body, and tissue deposition in inflammation. MPs are encountered only in bone and cartilagenous tissues, in which they are referred to as osteoclasts, odontoclasts, in which they are referred to as osteoclasts, odontoclasts, and septoclasts. Depending on the disease, the MPs differentiate into many morphological variants that include foreign-body giant cells, Langhans-type cells, and Touton-type cells. Morphological heterogeneity of MPs could Touton-type cells. Morphological heterogeneity of MPs could reflect the giant cell formation from phenotypically different marophage precursors by the process of fusion. At present, many cytokines, adhesion/fusion molecules, and other factors of the microenvironment have been discovered that influence the multinucleation process. Many evidences suggest that conditions in giant cell fibrohistiocytomas, which facilitate MP formation, are similar to the inflammation site of granulomatosis. MPs in the giant cell tumors and granulomatosis foci are formed in response to the factors secreted by mesenchymal cells. It is proposed that one of the first steps in vertebrate evolution could be the organization of skeleton remodeling, in which osteoclasts play a major role. In this step, the same mechanism of regulations served as a basis for the development of both osteoclast and inflammatory forms of MPs.