Multinucleated giant cells (MGCs), characteristic of granulomatous infections as well as multinucleated osteoclasts originate from fusion of macrophages. While intracellular and viral membrane fusion have been studied in detail, much less is known about the machinery which mediates cell-to-cell fusion, in particular macrophage polykaryon formation. Several molecules have been implicated in this process which may involve the action of multiple glycoproteins mediating membrane attachment and fusion. Macrophage fusion can be induced by soluble mediators such as cytokines and growth factors, even though several other stimuli may be involved, especially for the induction of granuloma-associated giant cells. The function of MGCs during granulomatous diseases is currently unknown. However, a better understanding of the mechanistic basis of macrophage fusion may lead to a better understanding of the function of MGCs found in granulomas.