While less appreciated than the ubiquitous process of cell fission (division), cell fusion events play crucial roles in all walks of life. In vertebrates, the multinucleated product of cell—cell fusion, referred to as a syncytium, is central to the structure and function of tissue types like skeletal muscle fibers and the fetal—maternal barrier in the placenta [1]. Syncytia have also been linked with cellular pathology in states of disease, such as HIV/AIDS. In this Pearl, we review and reconsider the controversial roles that cellular syncytia play in the replication and pathogenesis of HIV-1 infection. Furthermore, we describe research highlighting viral and cellular regulators of this cell—cell fusion activity. Overall, our aim is to provide a scientific framework necessary for the further study and appreciation of what happens when viruses bring cells together (literally).