Junctional adhesion molecules are transmembrane proteins that belong to the immunoglobulin superfamily. In addition to their localization in close proximity to the tight junctions in endothelial and epithelial cells, junctional adhesion molecules are also expressed in circulating cells that do not form junctions, such as leukocytes and platelets. As a consequence, these proteins are associated not only with the permeability-regulating barrier function of the tight junctions, but also with other biologic processes, such as inflammatory reactions, responses to vascular injury, and tumor angiogenesis. Furthermore, because of their transmembrane topology, junctional adhesion molecules are poised both for receiving inputs from the cell interior (their expression, localization, and function being regulated in response to inflammatory cytokines and growth factors) and for translating extracellular adhesive events into functional responses. This review focuses on the different roles of junctional adhesion molecules in normal and pathologic conditions, with emphasis on inflammatory reactions and vascular responses to injury.