In mammals, cell fusion occurs among a limited number of cell types: sperm and oocytes during fertilization, trophoblasts during placenta formation, macrophages during giant cell and osteoclast formation and myoblasts in the formation of myofibers and myotubes. The molecular mechanisms involved in these membrane fusion events largely are unknown. This review will focus on the known molecules that regulate myoblast fusion with an emphasis on a novel signaling pathway involving the calcium-regulated transcription factor NFATC2 in the regulation of myoblast fusion.