Inflammation is associated with a decreased adhesion between endothelial cells in blood vessels and an increased adhesion of circulating leukocytes to vascular endothelium and to epithelia of internal organs. These changes lead to leukocyte extravasation and tissue transmigration. We propose that ephrins and Eph receptors play important, but underappreciated, signaling roles in these processes. At early stages of inflammation, EphA2 receptor and ephrin-B2 are overexpressed in endothelial and epithelial cells, thus leading to those events (expression of adhesion molecules on the cell surface and reorganization of the intracellular cytoskeleton) that cause cell repulsion and disruption of endothelial and epithelial barriers. At later stages of inflammation, expression of EphA1, EphA3, EphB3, and EphB4 on leukocytes and endothelial cells decreases, thus promoting adhesion of leukocytes to endothelial cells. Taking into consideration the abundance of ephrins and Eph receptors in tissues and the robustness of their signaling effects, the proposed involvement is likely to be substantial and may constitute a novel therapeutic target.