Most viruses infect their hosts by crossing the mucosal surfaces of the respiratory, gastrointestinal, or genital tracts, then spread—often through the bloodstream—to other organs; they are shed in bodily secretions to reach new hosts. At each stage in the cycle of infection viruses surmount significant anatomic barriers. This Minireview focuses on the role of intercellular junctions as barriers to virus dissemination, and the somewhat paradoxical observation that several viruses, rather than evading these barriers, target them directly by using junctional proteins as receptors.