Junctional adhesion molecules (JAMs) are immunoglobulin superfamily (IgSF) proteins expressed at cell junctions in epithelial and endothelial cells as well as on the surface of leukocytes, platelets, and erythrocytes. Evidence suggests JAM proteins are important for a variety of cellular processes, including tight junction assembly, leukocyte transmigration, platelet activation, angiogenesis and virus binding. This review will highlight what is currently known about the structure, function, and mechanism of action of JAM proteins as well as comment on potential directions for future JAM-related research.