EPH/EPHRIN signaling modulates both cell:cell and cell:medium tension, driven by actomyosin contractility to drive cellular organization. (A) Schematic of cell:cell contacts and the forces that modulate these contacts. EPHB2:EPHB2 homotypic contact is driven by increased cell:medium tension, while EPHRIN-B1:EPHRIN-B1 homotypic contact is driven by cell adhesion. EPHB2:EPHRIN-B1 heterotypic cell pairs show high cell:cell interfacial tension due to increased actomyosin contractility at the cell:cell interface. (B) High cell:cell interfacial tension between EPHB2- and EPHRIN-B1–expressing cells results in a minimization of contact between these cell populations. Together with increased EPHB2 homotypic affinity, this increased cortical tension, preventing the formation of stable heterotypic contacts, drives cell segregation.