The herpesviruses of humans and animals are large, enveloped virions with complex genetic organization that cause either lytic or latent infections. Of the many glycoproteins encoded by these viruses and incorporated into the virion envelope, glycoprotein B (gB) is the most highly conserved. Homologues of gB are encoded by the genomes of all the herpesviruses. gB is required for infectivity and functions in penetration of cells by promoting fusion of the virion and plasma membranes. Syncytium formation, a manifestation of fusion activity in virus-infected cells, results from mutations in gB or in certain other genes encoding glycoproteins and integral membrane proteins. The paradox that mutations in gB and other proteins cause the formation of syncytia can be explained by the hypothesis that gB normally participates in a multisubunit protein complex that controls fusion following a cascade of interactions with cell-surface receptors. Syncytium formation by altered forms of the components of this complex would be the result of less well-regulated events. Recent findings on the control of fusion in other virus systems, and on vesicle fusion in the normal cellular secretory pathway, support a model in which gB functions together with other viral proteins to form a hydrophobic fusion pore.