The evolution of JAM family members prior to the biochemical means to efficiently and extensively diversify antigen receptor genes, along with the structural similarities in the binding surfaces of virus receptors and immunoglobulins, provides strong support for the contention that viruses and perhaps other pathogens that engage IgSF receptors contributed to the selection of humoral mediators of adaptive immunity. These observations provide a new framework for understanding how pathogen-host interplay during a prolonged period of evolutionary struggle may have led to the development of antigen-specific immune responses in vertebrates.