Cell fusion into multinucleated giant cells (MGC) is an essential process that contributes to many important biological mechanisms in mammalians. In the bone and immune system, macrophages are endowed with a remarkable potential for cell fusion events as evidenced by their propensity to fuse with other cells and between themselves during both normal processes and disease. Macrophage fusion is critical for the normal development of multinucleated osteoclasts, the cells responsible for bone resorption. Macrophages from various tissue compartments also undergo fusion into MGC, a hallmark of granulomatous inflammation. To date, the mechanisms underlying macrophage fusion remain poorly understood. Receptor-ligand interactions are thought to mediate this process and several lines of evidence implicate purinergic receptors in both osteoclast and MGC formation. Notably, the P2X7 receptor for extracellular ATP is expressed in osteoclasts and in many types of granulomas associated with infection, foreign body response and sterile inflammation. Through their ability to sense extracellular cues and ATP, a messenger of intercellular communication, purinergic receptors likely contribute to cell-cell interactions that result in macrophage fusion.